Thiophene derivatives as factor XIa inhibitors

ABSTRACT

The present invention provides compounds of Formula (I): 
                         
or stereoisomers, tautomers, pharmaceutically acceptable salts, solvates, or prodrugs thereof, wherein the variables A, L 1 , R 3 , and R 11  are as defined herein. The compounds of Formula (I) are useful as selective inhibitors of serine protease enzymes of the coagulation cascade and/or contact activation system; for example thrombin, factor Xa, factor XIa, factor IXa, factor VIIa and/or plasma kallikrein. In particular, it relates to compounds that are selective factor XIa inhibitors. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating thromboembolic and/or inflammatory disorders using the same.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a 371 application of PCT/US2006/061970 filed Dec.13, 2006, which claims priority benefit of U.S. provisional applicationSer. No. 60/750,131, filed Dec. 14, 2005, which is incorporated byreference herein.

FIELD OF THE INVENTION

The present invention relates generally to novel thiophene derivatives,and analogues thereof, which are useful as selective inhibitors ofserine protease enzymes of the coagulation cascade and/or contactactivation system; for example thrombin, factor XIa, factor Xa, factorIXa and/or factor VIIa, and/or plasma kallikrein. In particular, itrelates to compounds that are selective factor XIa inhibitors or dualinhibitors of fXIa and plasma kallikrein. This invention also relates topharmaceutical compositions comprising these compounds and methods ofusing the same.

BACKGROUND OF THE INVENTION

Factor XIa is a plasma serine protease involved in the regulation ofblood coagulation. While blood coagulation is essential to theregulation of an organism's hemostasis, it is also involved in manypathological conditions. In thrombosis, a blood clot, or thrombus, mayform and obstruct circulation locally, causing ischemia and organdamage. Alternatively, in a process known as embolism, the clot maydislodge and subsequently become trapped in a distal vessel, where itagain causes ischemia and organ damage. Diseases arising frompathological thrombus formation are collectively referred to asthrombotic or thromboembolic disorders and include acute coronarysyndrome, unstable angina, myocardial infarction, thrombosis in thecavity of the heart, ischemic stroke, deep vein thrombosis, peripheralocclusive arterial disease, transient ischemic attack, and pulmonaryembolism. In addition, thrombosis occurs on artificial surfaces incontact with blood, including catheters and artificial heart valves.Therefore, drugs that inhibit blood coagulation, or anticoagulants, are“pivotal agents for prevention and treatment of thromboembolicdisorders” (Hirsh, J. et al. Blood 2005, 105, 453-463). Thromboembolicdisorders are the largest cause of mortality and disability in theindustrialized world.

Blood coagulation is initiated in vivo by the binding of tissue factor(TF) to Factor VII (FVII) to generate Factor VIIa (FVIIa). The resultingTF:FVIIa complex activates Factor IX (FIX) and Factor X (FX) which leadsto the production of Factor Xa (FXa). The FXa that is generatedcatalyzes the transformation of prothrombin into small amounts ofthrombin before this pathway is shut down by tissue factor pathwayinhibitor (TFPI). The process of coagulation is then further propagatedvia the feedback activation of Factors V, VIII and XI by catalyticamounts of thrombin. (Walsh, P. N. Thromb. Haemostasis. 1999, 82,234-242.) The resulting burst of thrombin coverts fibrinogen to fibrin,which polymerizes to form the structural framework of a blood clot, andactivates platelets, which are a key cellular component of coagulation(Hoffman, M. Blood Reviews 2003, 17, S1-S5). Factor XIa plays a key rolein propagating this amplification loop and is thus an attractive targetfor anti-thrombotic therapy.

An alternative way of initiation of coagulation is operative when bloodis exposed to artificial surfaces (e.g., during hemodialysis, ‘on-pump’cardiovascular surgery, vessel grafts, bacterial sepsis), on cellsurfaces, cellular receptors, and extracellular matrices. This processis also termed contact activation. Surface absorption of factor XIIleads to a conformational change in the factor XII molecule, therebyfacilitating activation to proteolytic active factor XII molecules(factor XIIa and factor XIIf). Factor XIIa (or XIIf) has a number oftarget proteins, including plasma prekallikrein and factor XI. Activeplasma kallikrein further activates factor XII, leading to anamplification of contact activation. Alternatively, the serine proteaseprolylcarboxylpeptidase can activate plasma kallikrein complexed withhigh molecular weight kininogen in a multiprotein complex formed on thesurface of cells and matrices (Shariat-Madar et al. Blood 2006, 108,192-199). Contact activation is a surface mediated process responsiblein part for the regulation of thrombosis and inflammation, and ismediated, at least in part, by fibrinolytic-, complement-,kininogen/kinin-, and other humoral and cellular pathways (for review,Coleman, R. Contact Activation Pathway, pages 103-122 in Hemostasis andThrombosis, Lippincott Williams & Wilkins 2001; Schmaier A. H. ContactActivation, pages 105-128 in Thrombosis and Hemorrhage, 1998). Thebiological relevance of the contact activation system for thromboembolicdiseases is supported by the phenotype of factor XII deficient mice.More specifically, factor XII deficient mice were protected fromthrombotic vascular occlusion in several thrombosis models as well asstroke models and the phenotype of the XII deficient mice was identicalto XI deficient mice (Renne et al. J. Exp. Medicine 2005, 202, 271-281;Kleinschmitz et al. J. Exp. l Medicine, 2006, 203, 513-518). The factthat factor XI is down-stream from factor XIIa, combined with theidentical phenotype of the XII and XI deficient mice suggest that thecontact activation system could play a major role in factor XIactivation in vivo.

Factor XI is a zymogen of a trypsin-like serine protease and is presentin plasma at a relatively low concentration. Proteolytic activation atan internal R369-I370 bond yields a heavy chain (369 amino acids) and alight chain (238 amino acids). The latter contains a typicaltrypsin-like catalytic triad (H413, D464, and S557). Activation offactor XI by thrombin is believed to occur on negatively chargedsurfaces, most likely on the surface of activated platelets. Plateletscontain high affinity (0.8 nM) specific sites (130-500/platelet) foractivated factor XI. After activation, factor XIa remains surface boundand recognizes factor IX as its normal macromolecular substrate.(Galiani, D. Trends Cardiovasc. Med. 2000, 10, 198-204.)

In addition to the feedback activation mechanisms described above,thrombin activates thrombin activated fibrinolysis inhibitor (TAFI), aplasma carboxypeptidase that cleaves C-terminal lysine and arginineresidues on fibrin, reducing the ability of fibrin to enhancetissue-type plasminogen activator (tPA) dependent plasminogenactivation. In the presence of antibodies to FXIa, clot lysis can occurmore rapidly independent of plasma TAFI concentration. (Bouma, B. N. etal. Thromb. Res. 2001, 101, 329-354.) Thus, inhibitors of factor XIa areexpected to be anticoagulant and profibrinolytic.

Further evidence for the anti-thromboembolic effects of targeting factorXI is derived from mice deficient in factor XI. It has been demonstratedthat complete fXI deficiency protected mice from ferric chloride(FeCl₃)-induced carotid artery thrombosis (Rosen et al. Thromb Haemost2002, 87, 774-77; Wang et al., J Thromb Haemost 2005, 3, 695-702). Also,factor XI deficiency rescues the perinatal lethal phenotype of completeprotein C deficiency (Chan et al., Amer. J. Pathology 2001, 158,469-479). Furthermore, baboon cross-reactive, function blockingantibodies to human factor XI protect against baboon arterial—venousshunt thrombosis (Gruber et al., Blood 2003, 102, 953-955). Evidence foran antithrombotic effect of small molecule inhibitors of factor XIa isalso disclosed in published U.S. Patent Application US20040180855A1.Taken together, these studies suggest that targeting factor XI willreduce the propensity for thrombotic and thromboembolic diseases.

Genetic evidence indicates that factor XI is not required for normalhomeostasis, implying a superior safety profile of the factor XImechanism compared to competing antithrombotic mechanisms. In contrastto hemophilia A (factor VIII deficiency) or hemophilia B (factor IXdeficiency), mutations of the factor XI gene causing factor XIdeficiency (hemophilia C) result in only a mild to moderate bleedingdiathesis characterized primarily by postoperative or posttraumatic, butrarely spontaneous hemorrhage. Postoperative bleeding occurs mostly intissue with high concentrations of endogenous fibrinolytic activity(e.g. oral cavity, and urogenital system). The majority of the cases arefortuitously identified by preoperative prolongation of APTT (intrinsicsystem) without any prior bleeding history.

The increased safety of inhibition of XIa as an anticoagulation therapyis further supported by the fact that Factor XI knock-out mice, whichhave no detectable factor XI protein, undergo normal development, andhave a normal life span. No evidence for spontaneous bleeding has beennoted. The APTT (intrinsic system) is prolonged in a gene dose-dependentfashion. Interestingly, even after severe stimulation of the coagulationsystem (tail transection), the bleeding time is not significantlyprolonged compared to wild-type and heterozygous litter mates. (Gailani,D. Frontiers in Bioscience 2001, 6, 201-207; Gailani, D. et al. BloodCoagulation and Fibrinolysis 1997, 8, 134-144.) Taken together, theseobservations suggest that high levels of inhibition of factor XIa shouldbe well tolerated. This is in contrast to gene targeting experimentswith other coagulation factors.

In vivo activation of factor XI can be determined by complex formationwith either CI inhibitor or alpha 1 antitrypsin. In a study of 50patients with acute myocardial infarction (AMI), approximately 25% ofthe patients had values above the upper normal range of the complexELISA. This study can be viewed as evidence that at least in asubpopulation of patients with AMI, factor XI activation contributes tothrombin formation (Minnema, M. C. et al. Arterioscler. Thromb. Vasc.Biol. 2000, 20, 2489-2493). A second study establishes a positivecorrelation between the extent of coronary arteriosclerosis and factorXIa in complex with alpha 1 antitrypsin (Murakami, T. et al.Arterioscler Thromb Vasc Biol 1995, 15, 1107-1113.). In another study,Factor XI levels above the 90^(th) percentile in patients wereassociated with a 2.2-fold increased risk for venous thrombosis(Meijers, J. C. M. et al. N. Engl. J. Med. 2000, 342, 696-701.).

Plasma kallikrein is a zymogen of a trypsin-like serine protease and ispresent in plasma at 35 to 50 μg/mL. The gene structure is similar tothat of factor XI. Overall, the amino acid sequence of plasma kallikreinhas 58% homology to factor XI. Proteolytic activation by factor XIIa atan internal I 389-R390 bond yields a heavy chain (371 amino acids) and alight chain (248 amino acids). The active site of plasma kallikrein iscontained in the light chain. The light chain of plasma kallikreinreacts with protease inhibitors, including alpha 2 macroglobulin andC1-inhibitor. Interestingly, heparin significantly accelerates theinhibition of plasma kallikrein by antithrombin III in the presence ofhigh molecular weight kininogen (HMWK). In blood, the majority of plasmakallikrein circulates in complex with HMWK. Kallikrein cleaves HMWK toliberate bradykinin. Bradykinin release results in increase of vascularpermeability and vasodilation (for review, Coleman, R. ContactActivation Pathway, pages 103-122 in Hemostasis and Thrombosis,Lippincott Williams & Wilkins 2001; Schmaier A. H. Contact Activation,pages 105-128 in Thrombosis and Hemorrhage, 1998).

Proteins or peptides that reportedly inhibit Factor XIa are disclosed inWO 01/27079. There are advantages in using small organic compounds,however, in preparing pharmaceuticals, e.g., small compounds generallyhave better oral bioavailability and compatibility in makingformulations to aid in delivery of the drug as compared with largeproteins or peptides. Small molecule inhibitors of Factor XIa aredisclosed in U.S. Patent Application Publications, e.g.,US20040235847A1, US20040220206A1, US20050228000A1, US20060009455A1, andUS20050282805A1.

In addition, it is also desirable to find new compounds with improvedpharmacological characteristics compared with known serine proteaseinhibitors. For example, it is preferred to find new compounds withimproved factor XIa inhibitory activity and selectivity for factor XIaversus other serine proteases. Also, it is preferred to find newcompounds with improved plasma kallikrein inhibitory activity andselectivity for plasma kallikrein versus other serine proteases. It isalso desirable and preferable to find compounds with advantageous andimproved characteristics in one or more of the following categories,which are given as examples and are not intended to be limiting: (a)pharmacokinetic properties, including oral bioavailability; (b)pharmaceutical properties; (c) dosage requirements; (d) factors whichdecrease blood concentration peak-to-trough characteristics; (e) factorsthat increase the concentration of active drug at the receptor; (f)factors that decrease the liability for clinical drug-drug interactions;(g) factors that decrease the potential for adverse side-effects; and(h) factors that improve manufacturing costs or feasibility.

SUMMARY OF THE INVENTION

The present invention provides novel thiophene derivatives, andanalogues thereof, which are useful as selective inhibitors of serineprotease enzymes, especially factor XIa and/or plasma kallikrein, orstereoisomers, tautomers, pharmaceutically acceptable salts, solvates,or prodrugs thereof.

The present invention also provides processes and intermediates formaking the compounds of the present invention or stereoisomers,tautomers, pharmaceutically acceptable salts, solvates, or prodrugsthereof.

The present invention also provides pharmaceutical compositionscomprising a pharmaceutically acceptable carrier and at least one of thecompounds of the present invention or stereoisomers, tautomers,pharmaceutically acceptable salts, solvates, or prodrugs thereof.

The present invention also provides a method for modulation of thecoagulation cascade and/or the contact activation system comprisingadministering to a host in need of such treatment a therapeuticallyeffective amount of at least one of the compounds of the presentinvention or stereoisomers, tautomers, pharmaceutically acceptablesalts, solvates, or prodrugs thereof.

The present invention also provides a method for treating thromboembolicdisorders comprising administering to a host in need of such treatment atherapeutically effective amount of at least one of the compounds of thepresent invention or stereoisomers, tautomers, pharmaceuticallyacceptable salts, solvates, or prodrugs thereof.

The present invention also provides a method for treating inflammatorydiseases disorders comprising administering to a host in need of suchtreatment a therapeutically effective amount of at least one of thecompounds of the present invention or stereoisomers, tautomers,pharmaceutically acceptable salts, solvates, or prodrugs thereof.

The present invention also provides the compounds of the presentinvention or stereoisomers, tautomers, pharmaceutically acceptablesalts, solvates, or prodrugs thereof, for use in therapy.

The present invention also provides the use of the compounds of thepresent invention or stereoisomers, tautomers, pharmaceuticallyacceptable salts, solvates, or prodrugs thereof, for the manufacture ofa medicament for the treatment of a thromboembolic disorder.

The present invention also provides the use of the compounds of thepresent invention or stereoisomers, tautomers, pharmaceuticallyacceptable salts, solvates, or prodrugs thereof, for the manufacture ofa medicament for the treatment of an inflammatory disorder.

These and other features of the invention will be set forth in theexpanded form as the disclosure continues.

DETAILED DESCRIPTION OF THE INVENTION

In a first aspect, the present invention provides, inter alia, compoundsof Formula (I):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

A is substituted with 0-1 R¹ and 0-3 R² and is selected from the group:C₃₋₇ cycloalkyl, C₃₋₇ cycloalkenyl, phenyl, naphthyl, or a 5- to10-membered heterocycle comprising: carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p);

optionally, the thiophene ring is further substituted with 0-2 R⁴;

L₁ is a bond, —CH₂—, —CH₂CH₂—, —CH(NR⁷R⁸)CH₂—, —CH═CH—, —C≡C—, —OCH₂—,—CR⁵R⁶NH—, —CH₂O—, —SCH₂—, —SO₂CH₂—, —CH₂NR¹⁰—, or —NHNH—;

R¹ is, independently at each occurrence, H, —NH₂, —NH(C₁₋₃ alkyl),—(CH₂)_(r)NR⁷R⁸, —(CH₂)_(r)NR⁷C(O)OR⁹, —CH(C₁₋₄ alkyl)NH₂, —CH(C₁₋₄alkyl)₂NH₂, —N(C₁₋₃ alkyl)₂, —C(═NH)NH₂, —C(O)NH₂, —CH₂NH₂, —CH₂NH(C₁₋₃alkyl), —CH₂N(C₁₋₃ alkyl)₂, —CH₂CH₂NH₂, —CH₂CH₂NH(C₁₋₃ alkyl),—CH₂CH₂N(C₁₋₃ alkyl)₂, —C(═NR^(8a))NR⁸R⁹, —NR⁸CR⁸(═NR^(8a)), —NR⁷R⁸,—C(O)NR⁷R⁸, —S(O)_(p)NR⁸R⁹, F, Cl, Br, I, OCF₃, CF₃, OR^(a), SR^(a), CNor C₁₋₆ alkyl substituted with 0-1 R^(1a);

R^(1a) is —C(═NR^(8a))NR⁸R⁹, —NHC(═NR^(8a))NR⁸R⁹, —NR⁸CH(═NR^(8a)),—ONHC(═NR^(8a))NR⁸R⁹, —NR⁷R⁸, —C(O)NR⁷R⁸, F, OCF₃, CF₃, OR^(a), SR^(a),CN, —NR⁸SO₂NR⁸R⁹, —NR⁸SO₂R^(c), or —(CF₂)_(r)CF₃;

R² is, independently at each occurrence, ═O, F, Cl, Br, I, OCF₃, CF₃,CHF₂, CN, NO₂, —(CH₂)_(r)OR^(a), —(CH₂)_(r)SR^(a), —(CH₂)_(r)C(O)R^(a),—(CH₂)_(r)C(O)OR^(a), —(CH₂)_(r)OC(O)R^(a), —(CH₂)_(r)NR⁷R⁸,—(CH₂)_(r)C(O)NR⁸R⁹, —(CH₂)_(r)NR⁸C(O)R^(c), —(CH₂)_(r)NR⁸C(O)OR^(c),—NR⁸C(O)NR⁸R^(c), —S(O)_(p)NR⁸R⁹, —NR⁸S(O)₂R^(c), —S(O)R^(c),—S(O)₂R^(c), C₁₋₆ alkyl substituted with 0-2 R^(2a), C₂₋₆ alkenylsubstituted with 0-2 R^(2a), C₂₋₆ alkynyl substituted with 0-2 R^(2a),—(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(2b), or—(CH₂)_(r)-5- to 10-membered heterocycle comprising: carbon atoms and1-4 heteroatoms selected from N, O, and S(O)_(p), wherein saidheterocycle is substituted with 0-3 R^(2b);

R^(2a) is, independently at each occurrence, H, F, Cl, Br, I, ═O, ═NR⁸,CN, OCF₃, CF₃, OR^(a), SR^(a), —NR⁷R⁸, —C(O)NR⁸R⁹, —NR⁸C(O)R^(c),—NR⁸C(O)OR^(c), —NR⁸C(O)NR⁸R^(c), —S(O)_(p)NR⁸R⁹, —NR⁸SO₂R^(c),—S(O)R^(c), or —S(O)₂R^(c);

R^(2b) is, independently at each occurrence, H, F, Cl, Br, I, ═O, ═NR⁸,—(CH₂)_(r) CN, —(CH₂)_(r)NO₂, —(CH₂)_(r)OR^(a), —(CH₂)_(r)SR^(a),—(CH₂)_(r)C(O)R^(a), —(CH₂)_(r)C(O)OR^(a), —(CH₂)_(r)OC(O)R^(a),—(CH₂)_(r)NR⁷R⁸, —(CH₂)_(r)C(O)NR⁸R⁹, —(CH₂)_(r)NR⁸C(O)R^(c),—(CH₂)_(r)S(O)_(p)NR⁸R⁹, —(CH₂)_(r)SO₂R^(c), —(CH₂)_(r)NR⁸SO₂NR⁸R⁹,—(CH₂)_(r)NR⁸SO₂R^(c), —(CF₂)_(r)CF₃, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, C₁₋₄ haloalkyl, or C₁₋₄ haloalkyloxy;

alternately, when R¹ and R² are substituted on adjacent ring atoms, theycan be taken together with the ring atoms to which they are attached toform a 5- to 7-membered carbocycle or heterocycle comprising: carbonatoms and 0-4 heteroatoms selected from N, O, and S(O)_(p), wherein saidcarbocycle or heterocycle is substituted with 0-2 R^(g);

R³ is phenyl substituted with 0-3 R^(3a) and 0-1 R^(3d), naphthylsubstituted with 0-3 R^(3a) and 0-1 R^(3d), or —(CH₂)_(r)-5- to12-membered heterocycle comprising: carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p), wherein said heterocycle issubstituted with 0-3 R^(3a) and 0-1 R^(3d);

R^(3a) is, independently at each occurrence, ═O, ═NR⁸, F, Cl, Br, I,OCF₃, CF₃, —(CH₂)_(r)CN, NO₂, —(CH₂)_(r)OR^(3b), —(CH₂)_(r)—SR^(3b),—(CH₂)_(r)NR⁷R⁸, —C(═NR^(8a))NR⁸R⁹, —NHC(═NR^(8a))NR⁸R⁹, —C(O)OR^(3b),—C(O)C₁₋₄ alkyl, —SO₂NHR^(3b), —SO₂NHCOR^(3c), —SO₂NHCO₂R^(3c),—CONHSO₂R^(3c), —NR⁸CR⁸(═NR^(8a)), —NHC(O)NR⁸R⁹,—(CH₂)_(r)NR⁸C(O)R^(3b), —(CH₂)_(r)NR⁸CO₂R^(3b),—(CH₂)_(r)S(O)_(p)NR⁸R⁹, —(CH₂)_(r)NR⁸S(O)_(p)R^(3c), —NHSO₂CF₃,—S(O)R^(3c), —S(O)₂R^(3c), —(CH₂)_(r)CO₂R^(3b), —(CH₂)_(r)OC(O)R^(3b),—(CH₂)_(r)C(O)NR⁸R⁹, —(CH₂)_(r)OC(O)NR⁸R⁹, —NHCOCF₃, —NHSO₂R^(3c),—CONHOR^(3b), C₁₋₄ haloalkyl, C₁₋₄ haloalkyloxy, C₁₋₆ alkyl substitutedby R^(3e), C₂₋₆ alkenyl substituted by R^(3e), C₁₋₆ alkynyl substitutedby R^(3e), C₃₋₆ cycloalkyl substituted by 0-1 R^(3d), —(CH₂)_(r)—C₆₋₁₀carbocycle substituted by 0-3 R^(3d) or —(CH₂)_(r)-5- to 10-memberedheterocycle comprising: carbon atoms and 1-4 heteroatoms selected fromN, O, and S(O)_(p), wherein said heterocycle is substituted with 0-3R^(3d);

alternately, when two R^(3a) groups are substituted on adjacent atoms,they can be taken together with the atoms to which they are attached toform a C₃₋₁₀ carbocycle substituted with 0-2 R^(3d), or a 5- to10-membered heterocycle comprising: carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p), wherein said heterocycle issubstituted with 0-2 R^(3d);

R^(3b) is, independently at each occurrence, H, C₁₋₆ alkyl substitutedwith 0-2 R^(3e), C₂₋₆ alkenyl substituted with 0-2 R^(3e), C₂₋₆ alkynylsubstituted with 0-2 R^(3e), —(CH₂)_(r)—C₃₋₁₀ carbocycle substitutedwith 0-3 R^(3d), or —(CH₂)_(r)-5- to 10-membered heterocycle comprising:carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p),wherein said heterocycle is substituted with 0-3 R^(3d);

R^(3c) is, independently at each occurrence, C₁₋₆ alkyl substituted with0-2 R^(3d), C₂₋₆ alkenyl substituted with 0-2 R^(3d), C₂₋₆ alkynylsubstituted with 0-2 R^(3d), —(CH₂)_(r)—C₃₋₁₀ carbocycle substitutedwith 0-3 R^(3d), or —(CH₂)_(r)-5- to 10-membered heterocycle comprising:carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p),wherein said heterocycle is substituted with 0-3 R^(3d);

R^(3d) is, independently at each occurrence, H, ═O, F, Cl, Br, CN, NO₂,—(CH₂)_(r)NR⁷R⁸, —(CH₂)_(r)OR^(a), —C(O)R^(a), —C(O)OR^(a), —OC(O)R^(a),—NR⁸C(O)R^(c), —C(O)NR⁸R⁹, —S(O)₂NR⁸R⁹, —NR⁷R⁸, —NR⁸S(O)₂NR⁸R⁹,—NR⁸S(O)₂R^(c), —S(O)_(p)R^(c), —(CF₂)_(r)CF₃, C₁₋₆ alkyl substitutedwith 0-2 R^(e), C₂₋₆ alkenyl substituted with 0-2 R^(e), C₂₋₆ alkynylsubstituted with 0-2 R^(e), —(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with0-3 R^(d), or —(CH₂)_(r)-5- to 10-membered heterocycle comprising:carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p),wherein said heterocycle is substituted with 0-3 R^(d);

R^(3e) is, independently at each occurrence, H, —(CH₂)_(r)OR^(a), F, ═O,CN, NO₂, —(CH₂)_(r)NR⁷R⁸, —C(O)R^(a), —C(O)OR^(a), —OC(O)R^(a),—NR⁸C(O)R^(c), —C(O)NR⁸R⁹, —S(O)₂NR⁸R⁹, —NR⁸S(O)₂NR⁸R⁹, —NR⁸S(O)₂R^(c),—S(O)_(p)R^(c), —(CF₂)_(r)CF₃, —(CH₂)_(r)—C₃₋₁₀ carbocycle substitutedwith 0-3 R^(d), or —(CH₂)_(r)-5- to 10-membered heterocycle comprising:carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p),wherein said heterocycle is substituted with 0-3 R^(d);

R⁴ is, independently at each occurrence, H, F, Cl, Br, I, CF₃, CN, NO₂,—(CH₂)_(r)OR^(a), —(CH₂)_(r)SR^(a), —(CH₂)_(r)C(O)R^(a),—(CH₂)_(r)C(O)OR^(a), —(CH₂)_(r)NR⁷R⁸, —(CH₂)_(r)C(O)NR⁸R⁹,—(CH₂)_(r)NR⁸C(O)R^(c), —(CH₂)_(r)NR⁸C(O)₂R^(b), —(CH₂)_(r)NR⁸C(O)NR⁸R⁹,C₁₋₆ alkyl substituted with 0-2 R^(4a), C₂₋₆ alkenyl substituted with0-2 R^(4a), C₂₋₆ alkynyl substituted with 0-2 R^(4a), —(CH₂)_(r)—C₃₋₁₀carbocycle substituted with 0-3 R^(4b), or —(CH₂)_(r)-5- to 10-memberedheterocycle comprising: carbon atoms and 1-4 heteroatoms selected fromN, O, and S(O)_(p), wherein said heterocycle is substituted with 0-3R^(4b);

R^(4a) is, independently at each occurrence, H, F, ═O, C₁₋₄ alkyl,OR^(a), SR^(a), CF₃, CN, NO₂, —C(O)R^(a), —C(O)OR^(a), —NR⁷R⁸,—C(O)NR⁸R⁹, —NR⁷C(O)R^(c), —S(O)_(p)NR⁸R⁹, —NR⁸S(O)_(p)R^(c),—S(O)R^(c), or —S(O)₂R^(c);

R^(4b) is, independently at each occurrence, H, ═O, ═NR⁸, OR², SR², F,Cl, Br, I, CN, NO₂, —NR⁷R⁸, —C(O)R^(a), —C(O)OR^(a), —NR⁷C(O)R^(c),—C(O)NR⁸R⁹, —SO₂NR⁸R⁹, —S(O)₂R^(c), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, C₁₋₄ haloalkyl, or C₁₋₄ haloalkyloxy;

R⁷ is, independently at each occurrence, H, C₁₋₆ alkyl, —(CH₂)_(n)—C₃₋₁₀carbocycle, —(CH₂)_(n)-(5- to 10-membered heteroaryl), —C(O)R^(c), —CHO,—C(O)₂R^(c), —S(O)₂R^(c), —CONR⁸R^(c), —OCONHR^(c), —C(O)O—(C₁₋₄alkyl)OC(O)—(C₁₋₄ alkyl), or —C(O)O—(C₁₋₄ alkyl)OC(O)—(C₆₋₁₀ aryl);wherein said alkyl, carbocycle, heteroaryl, and aryl are substitutedwith 0-2 R^(f); wherein said heteroaryl comprises: carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p);

R⁸ is, independently at each occurrence, H, C₁₋₆ alkyl,—(CH₂)_(n)-phenyl, or —(CH₂)_(n)-5- to 10-membered heterocyclecomprising: carbon atoms and 1-4 heteroatoms selected from N, O, andS(O)_(p); wherein said alkyl, phenyl and heterocycle are optionallysubstituted with 0-2 R^(f);

alternatively, R⁷ and R⁸, when attached to the same nitrogen, combine toform a 5- to 10-membered heterocycle comprising: carbon atoms and 0-3additional heteroatoms selected from N, O, and S(O)_(p), wherein saidheterocycle is substituted with 0-2 R^(f);

R^(8a) is, independently at each occurrence, R⁷, OH, C₁₋₄ alkoxy, (C₆₋₁₀aryl)-C₁₋₄ alkoxy; wherein said aryl is optionally substituted with 0-2R^(f);

R⁹ is, independently at each occurrence, H, C₁₋₆ alkyl, or—(CH₂)_(X)-phenyl; wherein said alkyl and phenyl are optionallysubstituted with 0-2 R^(f);

alternatively, R⁸ and R⁹, when attached to the same nitrogen, combine toform a 5- to 12-membered heterocycle comprising: carbon atoms and 0-2additional heteroatoms selected from N, O, and S(O)_(p), wherein saidheterocycle is substituted with 0-2 R^(d);

R¹⁰ is, independently at each occurrence, H, C₁₋₆ alkyl substituted with0-2 R^(10a), —(CH₂)_(r)-phenyl substituted with 0-3 R^(d), or—(CH₂)_(r)-5- to 10-membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), and substituted with 0-3R^(d);

R^(10a) is, independently at each occurrence, H, ═O, C₁₋₄ alkyl, OR^(a),SR^(a), F, CF₃, CN, NO₂, —C(O)R^(a), —C(O)OR^(a), —C(O)NR⁸R⁹,—NR⁸C(O)R^(c), —S(O)_(p)NR⁸R⁹, —NR⁸S(O)_(p)R^(c), or —S(O)_(p)R^(c);

R¹¹ is C₁₋₄haloalkyl, —C(O)NR⁸R⁹, —CH₂C(O)NR⁸R⁹, —CH₂CH₂C(O)NR⁸R⁹,—C(O)R^(a), —CH₂C(O)R^(a), —CH₂CH₂C(O)R^(a), —C(O)OR^(a),—CH₂C(O)OR^(a), —CH₂CH₂C(O)OR^(a), C₁₋₆ alkyl substituted with 0-3R^(11c), C₂₋₆ alkenyl substituted with 0-3 R^(11a); C₂₋₆ alkynylsubstituted with 0-3 R^(11a), —(CH₂)_(s)—C₃₋₇ cycloalkyl substitutedwith 0-2 R^(11b), —(CH₂)_(s)-phenyl substituted with 0-3 R^(11b),—(CH₂)_(s)-naphthyl substituted with 0-3 R^(11b), or —(CH₂)_(s)-5- to10-membered heterocycle comprising: carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p), wherein said heterocycle issubstituted with 0-3 R^(11b);

R^(11a) is, independently at each occurrence, H, ═O, C₁₋₄ alkyl, OR^(a),SR^(a), F, CF₃, CN, NO₂, —NR⁷R⁸, —C(O)R^(a), —C(O)OR^(a), —C(O)NR⁸R⁹,—NR⁸C(O)R^(c), —NR⁸C(O)OR^(c), —NR⁸CHO, —S(O)_(p)NR⁸R⁹,—NR⁸S(O)_(p)R^(c), —S(O)_(p)R^(c), C₃₋₆ cycloalkyl, C₁₋₄ haloalkyl, C₁₋₄haloalkyloxy, —(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(d), or—(CH₂)_(r)-5- to 10-membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), and substituted with 0-3R^(d);

R^(11b) is, independently at each occurrence, H, ═O, ═NR⁸, OR², SR², F,Cl, Br, CN, NO₂, CF₃, OCF₃, OCHF₂, —NR⁷R⁸, —C(O)R^(a), —C(O)OR^(a),—C(O)NR⁸R⁹, —NR⁸C(O)R^(c), —NR⁸C(O)₂R^(c), —S(O)_(p)NR⁸R⁹,—NR⁸S(O)_(p)R^(c), —S(O)_(p)R^(c), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkyloxy,—(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(d), or —(CH₂)_(r)-5-to 10-membered heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p), and substituted with 0-3 R^(d);

alternately, when two R^(11b) groups are substituents on adjacent atomsthey may be taken together with the atoms to which they are attached toform a 5- to 7-membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p) and substituted with 0-2R^(g);

R^(11c) is, independently at each occurrence H, ═O, OR^(a), SR^(a), F,CF₃, CN, NO₂, —NR⁷R⁸, —NR⁸C(O)R^(c), —NR⁸C(O)OR^(c), —NR⁸CHO,—S(O)_(p)NR⁸R⁹, —NR⁸S(O)_(p)R^(c), —S(O)_(p)R^(c), C₁₋₄ alkyl, C₃₋₆cycloalkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkyloxy, —(CH₂)_(r)—C₃₋₁₀carbocycle substituted with 0-3 R^(d), or —(CH₂)_(r)-5- to 10-memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,O, and S(O)_(p), and substituted with 0-3 R^(d);

R^(a) is, independently at each occurrence, H, CF₃, C₁₋₆ alkyl,—(CH₂)_(r)—C₃₋₇ cycloalkyl, —(CH₂)_(r)—C₆₋₁₀ aryl, or —(CH₂)_(r)-5- to10-membered heteroaryl comprising carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p); wherein said cycloalkyl, aryl orheteroaryl groups are optionally substituted with 0-2 R^(f);

R^(b) is, independently at each occurrence, CF₃, OH, C₁₋₄ alkoxy, C₁₋₆alkyl, —(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(d), or—(CH₂)_(r)-5- to 10-membered heterocycle comprising: carbon atoms and1-4 heteroatoms selected from N, O, and S(O)_(p) and substituted with0-3 R^(d);

R^(c) is, independently at each occurrence, CF₃, C₁₋₆ alkyl substitutedwith 0-2 R^(f), C₃₋₆ cycloalkyl substituted with 0-2 R^(f), C₆₋₁₀ aryl,5- to 10-membered heteroaryl, (C₆₋₁₀ aryl)-C₁₋₄ alkyl, or (5- to10-membered heteroaryl)-C₁₋₄ alkyl, wherein said aryl is substitutedwith 0-3 R^(f) and said heteroaryl comprises: carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p) and substituted with 0-3R^(f);

R^(d) is, independently at each occurrence, H, ═O, ═NR⁸, OR^(a), F, Cl,Br, I, CN, NO₂, —NR⁷R⁸, —C(O)R^(a), —C(O)OR^(a), —OC(O)R^(a),—NR⁸C(O)R^(c), —C(O)NR⁸R⁹, —SO₂NR⁸R⁹, —NR⁸SO₂NR⁸R⁹, —NR⁸SO₂—C₁₋₄ alkyl,—NR⁸SO₂CF₃, —NR⁸SO₂-phenyl, —S(O)₂CF₃, —S(O)_(p)—C₁₋₄ alkyl,—S(O)_(p)-phenyl, —(CF₂)_(r)CF₃, C₁₋₆ alkyl substituted with 0-2 R^(e),C₂₋₆ alkenyl substituted with 0-2 R^(e), or C₂₋₆ alkynyl substitutedwith 0-2 R^(e);

R^(e) is, independently at each occurrence, ═O, OR^(a), F, Cl, Br, I,CN, NO₂, —NR⁷R⁸, —C(O)R^(a), —C(O)OR^(a), —NR⁸C(O)R^(c), —C(O)NR⁸R⁹,—SO₂NR⁸R⁹, —NR⁸SO₂NR⁸R⁹, —NR⁸SO₂—C₁₋₄ alkyl, —NR⁸SO₂CF₃, —NR⁸SO₂-phenyl,—S(O)₂CF₃, —S(O)_(p)—C₁₋₄ alkyl, —S(O)_(p)-phenyl, or —(CF₂)_(r)CF₃;

R^(f) is, independently at each occurrence, H, ═O, —(CH₂)_(r)OR^(g), F,Cl, Br, I, CN, NO₂, —NR^(g)R^(g), —C(O)R9, —C(O)OR^(g),—NR^(g)C(O)R^(g), —C(O)NR^(g)R^(g), —SO₂NR^(g)R^(g),—NR^(g)SO₂NR^(g)R^(g), —NR^(g)SO₂—C₁₋₄ alkyl, —NR^(g)SO₂CF₃,—NR^(g)SO₂-phenyl, —S(O)₂CF₃, —S(O)_(p)—C₁₋₄ alkyl, —S(O)_(p)-phenyl,—(CH₂) n-phenyl, —(CF₂)_(r)CF₃, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆ alkynyl,—(CH₂)_(n)-phenyl, or —(CH₂)_(n)-5- to 10-membered heterocyclecomprising carbon atoms and 1-4 heteroatoms selected from N, O, andS(O)_(p);

alternately, when two R^(f) groups are substituents on adjacent atomsthey may be taken together with the atoms to which they are attached toform a 5-7-membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p) and substituted with 0-2R⁹;

R^(g) is, independently at each occurrence, H, C₁₋₆ alkyl, or—(CH₂)_(n)-phenyl;

n, at each occurrence, is selected from 0, 1, 2, 3, and 4;

p, at each occurrence, is selected from 0, 1, and 2; and

r, at each occurrence, is selected from 0, 1, 2, 3, and 4; and

s, at each occurrence, is selected from 1, 2, 3, and 4;

provided that: when R¹¹ is —CH₂CO₂H, L₁ is other than —CH₂O— (CASRegistry Nos. 778606-28-3, 777937-24-3).

In a second aspect, the present invention includes compounds of Formula(I) or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, within the scope of the first aspectwherein:

R⁴ is, independently at each occurrence, H, Me, Et, F, Cl, Br, I, CF₃,CN, NO₂, —CH₂OH, —CH₂C(O)OR^(a), OR^(a), SR^(a), —C(O)R^(a),—C(O)OR^(a), —(CH₂)_(r)NH₂, —(CH₂)_(r)C(O)NR⁸R⁹, or phenyl substitutedwith 0-2 R^(4b);

R^(4b) is, independently at each occurrence, H, F, Cl, Br, I, OR^(a),SR^(a), CN, NO₂, —NR⁷R⁸, —C(O)R^(a), —C(O)OR^(a), —NR⁷C(O)R^(b),—NR⁷C(O)OR^(c), —C(O)NR⁸R⁹, —SO₂NR⁸R⁹, —S(O)₂R^(c), C₁₋₄ alkyl, C₃₋₆cycloalkyl, C₁₋₄ haloalkyl, or C₁₋₄ haloalkyloxy; and

R¹¹ is C₁₋₄ haloalkyl, —CH₂C(O)NR⁸R⁹, —CH₂CH₂C(O)NR⁸R⁹, —CH₂C(O)R^(a),—CH₂CH₂C(O)R^(a), —CH₂C(O)OR^(a), —CH₂CH₂C(O)OR^(a), C₁₋₆ alkylsubstituted with 0-2 R^(11c), C₂₋₆ alkenyl substituted with 0-2 R^(11a),C₂₋₆ alkynyl substituted with 0-2 R^(11a), —(CH₂)_(r)—C₃₋₁₀ carbocyclesubstituted with 0-3 R^(11b), or —(CH₂)_(r)-5- to 10-memberedheterocycle comprising: carbon atoms and 1-4 heteroatoms selected fromN, O, and S(O)_(p), wherein said heterocycle is substituted with 0-3R^(11b).

In a third aspect, the present invention includes compounds of Formula(I) or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, within the scope of the first or secondaspect wherein:

L₁ is a bond, —CH₂—, —CH₂CH₂—, —CH═CH—, —C≡C—, —OCH₂—, —CH₂NH—, —CH₂O—,—SCH₂—, —SO₂CH₂—, or —NHNH—;

R¹ is, independently at each occurrence, F, Cl, Br, Me, Et, CF₃, OMe,OH, —NH₂, —C(═NH)NH₂, —C(O)NH₂, —CH₂NH₂, or —SO₂NH₂;

R² is, independently at each occurrence, F, Cl, Br, CF₃, NO₂,—(CH₂)_(r)OR^(a), —(CH₂)_(r)SR^(a), —C(O)OR^(a), —C(O)NR⁸R⁹,—NR⁸C(O)R^(c), —NR⁸C(O)OR^(c), —NR⁸C(O)NR⁸R^(c), —S(O)_(p)NR⁸R⁹,—NR⁸SO₂R^(c), —NR⁷R⁸, —S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl substitutedwith 0-1 R²², or a 5-7 membered heterocycle comprising carbon atoms and1-4 heteroatoms selected from N, O, and S(O)_(p), wherein saidheterocycle is substituted with 0-2 R^(2b);

alternately, when R¹ and R² groups are substituents on adjacent atomsthey may be taken together with the atoms to which they are attached toform a 5- to 7-membered carbocycle or heterocycle comprising carbonatoms and 0-4 heteroatoms selected from N, O, and S(O)_(p) andsubstituted with 0-2 R⁹;

R³ is phenyl substituted with 0-2 R^(3a) and 0-1 R^(3d), naphthylsubstituted with 0-2 R^(3a) and 0-1 R^(3d), or a 5- to 12-memberedheterocycle substituted with 0-2 R^(3a) and 0-1 R^(3d), wherein saidheterocycle is selected from: thiophene, furan, thiazole, tetrazole,pyridine, pyridone, pyrimidine, pyrrole, pyrazole, indole, 2-oxindole,isoindoline, indazole, 7-azaindole, benzofuran, benzothiophene,benzimidazole, benzisoxazole, benzoxazole, quinazoline, quinoline,isoquinoline, quinoxaline, phthalazine, dihydrophthalazine,dihydroisoquinoline, dihydroquinoline, dihydroquinolone, dihydroindole,dihydrobenzimidazole, dihydrobenzoxazine, dihydroquinazoline,dihydroquinoxaline, benzothiazine, benzoxazine, tetrahydrobenzazepine,dihydroazabenzocycloheptene, and tetrahydroquinoline;

R^(3a) is, independently at each occurrence, ═O, F, Cl, Br, Me, CN, OH,OMe, —OC(O)(t-Bu), —CH₂OMe, CF₃, COMe, CO₂H, CO₂Me, —CH₂CO₂H,—(CH₂)₂CO₂H, —CH₂CO₂Me, —CH₂CO₂Et, —CH₂CH₂CO₂Et, —CH₂CN, NH₂, —CH₂NH₂,—CH₂NMe₂, —NHCOMe, —NHCO₂Me, —NHCO₂Et, —NHCH₂CH₂CO₂H, —NHCO₂(i-Pr),—NHCO₂(1-Bu), —NHCO₂(t-Bu), —NHCO₂Bn, —NHCO₂CH₂CH₂OMe,—NHCO₂CH₂CH₂CH₂OMe, —NHCO₂CH₂CO₂H, —NHCO₂CH₂CH₂CO₂H, —NHCO₂CH₂CH₂OH,—NHCO₂CH₂CH₂NH₂, —NHCO₂CH₂-tetrahydrofuran-2-yl,—NHCO₂CH₂CH₂-morpholino, —CH₂NHCO₂Me, —NHC(O)NHMe, —NHC(O)N(Me)₂,4-[(1-carbamoyl-cyclopropanecarbonyl)-amino]-, —NHSO₂Me, —SO₂NH₂,SO₂NHMe, —SO₂NHCH₂CH₂OH, —CONH₂, —CONHMe, —CON(Me)₂, —C(O)NHCH₂CH₂OMe,—CH₂CONH₂, —CO(N-morpholino), —NHCH₂CH₂(N-morpholino), —NR⁷R⁸,—NH(1H-imidazol-2-yl), 1H-tetrazol-5-yl, tetrazol-1-yl, pyrimidin-5-yl,or N-morpholino;

R⁴ is, independently at each occurrence, H, F, Cl, Br, Me, Et, Pr, CN,CF₃, —CH₂OH, —(CH₂)₂OH, —(CH₂)₃OH, —CH₂NH₂, —(CH₂)₂NH₂, —(CH₂)₃NH₂,CO₂H, —C(O)NH₂, —C(O)NHMe, —C(O)N(Me)₂, —CH₂CO₂H, —CH₂C(O)NH₂,—CH₂CH₂CO₂H, and

R¹¹ is C₁₋₄ haloalkyl, —CH₂C(O)NR⁸R⁹, —CH₂CH₂C(O)NR⁸R⁹, —CH₂C(O)R^(a),—CH₂CH₂C(O)R^(c), —CH₂C(O)OR^(a), —CH₂CH₂C(O)OR^(a), C₁₋₆ alkylsubstituted with 0-2 R^(11c), —(CH₂)_(r)—C₃₋₇ cycloalkyl substitutedwith 0-2 R^(11b), —(CH₂)_(r)-indanyl substituted with 0-2 R^(11b),—(CH₂)_(r)-indenyl substituted with 0-2 R^(11b), —(CH₂)_(r)-phenylsubstituted with 0-2 R^(11b), —(CH₂)_(r)-naphthyl substituted with 0-2R^(11b), or —(CH₂)_(r)-5- to 10-membered heterocycle comprising carbonatoms and 1-4 heteroatoms selected from N, O, and S(O)_(p), wherein saidheterocycle is substituted with 0-2 R^(11b).

In a fourth aspect, the present invention includes compounds of Formula(I) or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, within the scope of the first aspectwherein:

A is substituted with 0-1 R¹ and 0-3 R² and selected from; C₃₋₇cycloalkyl, phenyl, naphthyl, pyridyl, 1,2,3,4-tetrahydronaphthyl,pyrrolidinyl, indazolyl, indolyl, imidazolyl, furanyl, thienyl,benzimidazolyl, benzisoxazolyl, benzothiazolyl, benzothiophenyl,3,4-methylenedioxy-phenyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, pyrazolyl, quinolinyl, isoquinolinyl,1H-4-oxo-isoquinazolinyl, 2H-1-oxo-isoquinolinyl, 3H-4-oxo-quinazolinyl,3,4-dihydro-2H-1-oxo-isoquinolinyl, 2,3-dihydro-isoindolinyl,5,6,7,8-tetrahydroquinolinyl, 1,2,3,4-tetrahydroquinolinyl,5,6,7,8-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,quinazolinyl, and phthalazinyl;

L₁ is a bond, —CH₂—, —CH₂CH₂—, —CH═CH—, —C≡C—, or —CH₂NH—;

R¹ is, independently at each occurrence, F, Cl, Br, CF₃, NH₂, —CH₂NH₂,—C(═NH)NH₂, —C(O)NH₂, —SO₂NH₂, SR^(a), OR^(a), or C₁₋₆ alkyl substitutedwith 0-1 R^(1a);

R² is, independently at each occurrence, ═O, F, Cl, Br, CF₃, Me, Et,OR^(a), CN, NO₂, NR⁷R⁸, —CH₂OMe, —SR^(a), —CH₂SMe, —C(O)OR^(a),—CH₂NR⁷R⁸, —SO₂NH₂, —SO₂Me, —NHSO₂R^(c), —CH₂NHSO₂R^(c), —C(O)NR⁸R⁹,—NHC(O)R^(c), —CH₂NHC(O)R^(c), —NHC(O)OR^(c), —CH₂NHC(O)OR^(c),—NHC(O)NHR^(c), —CH₂NHC(O)NHR^(c), or a 5-7 membered heterocyclesubstituted with 0-2 R^(2b) and selected from: pyrrolidinyl,2-oxo-1-pyrrolidinyl, piperidinyl, pyrazolyl, triazolyl, or tetrazolyl;

alternately, when R¹ and R² groups are substituents on adjacent atomsthey may be taken together with the atoms to which they are attached toform a 5- to 6-membered heterocycle comprising carbon atoms and 0-4heteroatoms selected from N, O, and S(O)_(p);

R³ is, independently at each occurrence, phenyl substituted with 0-2R^(3a), naphthyl substituted with 0-2 R^(3a), or a 5- to 12-memberedheterocycle comprising: carbon atoms and 1-2 heteroatoms selected fromN, O, and S(O)_(p), wherein said heterocycle is substituted with 0-2R^(3a);

R^(3a) is, independently at each occurrence, ═O, F, Cl, Br, Me, CN, OH,OMe, —OC(O)(t-Bu), —CH₂OMe, CF₃, COMe, CO₂H, CO₂Me, —CH₂CO₂H,—(CH₂)₂CO₂H, —CH₂CO₂Me, —CH₂CO₂Et, —CH₂CH₂CO₂Et, —CH₂CN, NH₂, —CH₂NH₂,—CH₂NMe₂, —NHCOMe, —NHCO₂Me, —NHCO₂Et, —NHCH₂CH₂CO₂H, —NHCO₂(i-Pr),—NHCO₂(1-Bu), —NHCO₂(t-Bu), —NHCO₂Bn, —NHCO₂CH₂CH₂OMe,—NHCO₂CH₂CH₂CH₂OMe, —NHCO₂CH₂CO₂H, —NHCO₂CH₂CH₂CO₂H, —NHCO₂CH₂CH₂OH,—NHCO₂CH₂CH₂NH₂, —NHCO₂CH₂-tetrahydrofuran-2-yl,—NHCO₂CH₂CH₂-morpholino, —CH₂NHCO₂Me, —NHC(O)NHMe, —NHC(O)N(Me)₂,4-[(1-carbamoyl-cyclopropanecarbonyl)-amino]-, —NHSO₂Me, —SO₂NH₂,SO₂NHMe, —SO₂NHCH₂CH₂OH, —CONH₂, —CONHMe, —CON(Me)₂, —C(O)NHCH₂CH₂OMe,—CH₂CONH₂, —CO(N-morpholino), —NHCH₂CH₂(N-morpholino), —NR⁷R⁸,—NH(1H-imidazol-2-yl), 1H-tetrazol-5-yl, tetrazol-1-yl, pyrimidin-5-yl,or N-morpholino, or —(CH₂)_(r)-5- to 6-membered heterocycle comprising:carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p),wherein said heterocycle is substituted with 0-1 R^(3d);

alternatively, two of R^(3a) groups located on adjacent atoms, they canbe taken together with the atoms to which they are attached to form a 5-to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p), wherein said heterocycle issubstituted with 0-2 R^(3d);

R⁴ is, independently at each occurrence, H, F, Cl, Br, Me, Et, Pr, CN,CF₃, —CH₂OH, —(CH₂)₂OH, —(CH₂)₃OH, —CH₂NH₂, —(CH₂)₂NH₂, —(CH₂)₃NH₂,CO₂H, —C(O)NH₂, —C(O)NHMe, —C(O)N(Me)₂, —CH₂CO₂H, —CH₂C(O)NH₂, or—CH₂CH₂CO₂H;

R¹¹ is C₁₋₄ haloalkyl, —CH₂C(O)NR⁸R⁹, —CH₂CH₂C(O)NR⁸R⁹, —CH₂C(O)R^(a),—CH₂CH₂C(O)R^(a), —CH₂C(O)OR^(a), —CH₂CH₂C(O)OR^(a), —CH₂OBn, —CH₂SBn,C₁₋₆ alkyl substituted with 0-2 R^(11c), C₂₋₆ alkenyl substituted with0-2 R^(11a), C₂₋₆ alkynyl substituted with 0-2 R^(11a), —(CH₂)_(r)—C₃₋₇cycloalkyl substituted with 0-2 R^(11b), —(CH₂)_(r)-phenyl substitutedwith 0-2 R^(11b), —(CH₂)_(r)-indanyl substituted with 0-2 R^(11b),—(CH₂)_(r)-indenyl substituted with 0-2 R^(11b), —(CH₂)_(r)-naphthylsubstituted with 0-2 R^(11b), or —(CH₂)_(r)-5- to 10-membered heteroarylsubstituted with 0-2 R^(11b) and selected from thiazolyl, oxazolyl,pyrazolyl, triazolyl, tetrazolyl, thiadiazolyl, isoxazolyl, imidazolyl,pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, indazolyl,isoindolyl, indolinyl, isoindolinyl, benzimidazolyl, benzothiazolyl,benzotriazolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and2,2-dioxo-2,3-dihydro-1H-2λ⁶-benzo[c]thiophenyl; and

R^(11b) is, independently at each occurrence, H, ═O, F, Cl, Br, CF₃,OMe, OEt, O(i-Pr), OCF₃, OCHF₂, CN, OPh, OBn, NO₂, NH₂, —C(O)R^(a),—C(O)OR^(a), —C(O)NR⁷R⁸, —NR⁸C(O)R^(c), —NR⁸C(O)₂R^(c), —S(O)_(p)NR⁸R⁹,—NR⁸S(O)_(p)R^(c), —S(O)_(p)R^(c), C₁₋₆ alkyl, or —(CH₂)_(r)—C₃₋₁₀carbocycle substituted with 0-3 R^(d); and

alternately, when two R^(11b) groups are substituents on adjacent atomsthey may be taken together with the atoms to which they are attached toform a 5- to 7-membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p) and substituted with 0-2R^(g).

In a fifth aspect, the present invention includes compounds of Formula(I) or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, within the scope of any of the first,second and fourth aspects wherein:

A is substituted with 0-1 R¹ and 0-3 R² and selected from; C₃₋₇cycloalkyl, phenyl, naphthyl, pyridyl, 1,2,3,4-tetrahydronaphthyl,pyrrolidinyl, indazolyl, indolyl, imidazolyl, furanyl, thienyl,benzimidazolyl, benzisoxazolyl, benzothiazolyl, benzothiophenyl,3,4-methylenedioxy-phenyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, pyrazolyl, quinolinyl, isoquinolinyl,1H-4-oxo-isoquinazolinyl, 2H-1-oxo-isoquinolinyl, 3H-4-oxo-quinazolinyl,3,4-dihydro-2H-1-oxo-isoquinolinyl, 2,3-dihydro-isoindolinyl,5,6,7,8-tetrahydroquinolinyl, 1,2,3,4-tetrahydroquinolinyl,5,6,7,8-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,quinazolinyl, and phthalazinyl;

R³ is, independently at each occurrence, phenyl, 3-biphenyl, 4-biphenyl,3-aminophenyl, 4-aminophenyl, 3-N,N-dimethylaminophenyl,4-phenoxyphenyl, 4-benzyloxyphenyl, 4-(t-butoxymethyl)-phenyl,4-methylsulfonylphenyl, 3-cyanophenyl, 4-cyanophenyl, 3-fluorophenyl,4-fluorophenyl, 3-chlorophenyl, 4-chlorophenyl, 3-bromophenyl,4-bromophenyl, 3-hydroxyphenyl, 4-hydroxyphenyl, 2-methoxyphenyl,3-methoxyphenyl, 4-methoxyphenyl, 3-trifluoromethylphenyl,4-trifluoromethylphenyl, 3-carboxyphenyl, 4-carboxyphenyl,3-methoxycarbonylphenyl, 4-methoxycarbonylphenyl, 3-carboxymethylphenyl,4-carboxymethylphenyl, 4-methoxycarbonylmethylphenyl,3-ethoxycarbonylmethylphenyl, 4-ethoxycarbonylmethylphenyl,4-ethoxycarbonylethylphenyl, 3-carbamoylphenyl, 4-carbamoylphenyl,3-aminocarbonylmethylphenyl, 4-aminocarbonylmethylphenyl,4-methylaminocarbonylphenyl, 4-dimethylaminocarbonylmethylphenyl,4-amidinophenyl, 3-methylcarbonylaminophenyl,4-methylcarbonylaminophenyl, 4-methoxycarbonylaminophenyl,4-aminosulfonylphenyl, 3-methylsulfonylaminophenyl,4-methylsulfonylamino, 2,4-difluorophenyl, 3-fluoro-4-cyanophenyl,4-amino-3-carboxyphenyl, 4-amino-3-methoxycarbonylphenyl,2,4-dichlorophenyl, 3-cyano-5-fluorophenyl, 3-fluoro-4-carbamoylphenyl,3-carboxy-4-cyanophenyl, 3-phenyl-4-carbamoylphenyl,4-(2-oxo-1-piperidino)-phenyl, thiazol-2-yl, thien-2-yl,4-methoxycarbonyl-thiazol-2-yl, 4-carbamoyl-thiazol-2-yl,1-benzyl-pyrazol-4-yl, 5-phenyl-oxazol-2-yl, 5-carbamoyl-thien-2-yl,5-carboxy-thien-2-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl,6-amino-pyrid-3-yl, benzimidazol-2-yl, 6-methoxy-pyrid-3-yl,1-methyl-benzimidazol-2-yl, benzoxazol-2-yl, benzothiazol-2-yl,3-amino-benzisoxazol-6-yl, 3-amino-benzisoxazol-5-yl, indazol-5-yl,indazol-6-yl, 3-amino-indazol-5-yl, 3-hydroxy-indazol-5-yl,3-amino-indazol-6-yl, 3-amino-1-methyl-indazol-6-yl,3-amino-4-fluoro-indazol-6-yl, 3-amino-5-fluoro-indazol-6-yl,3-amino-7-fluoro-indazol-6-yl,4-imino-3,4-dihydro-2H-phthalazin-1-on-7-yl, 3-(5-tetrazolyl)-phenyl,2,3-dihydro-isoindol-1-on-6-yl, quinolin-5-yl, quinolin-6-yl,quinolin-8-yl, isoquinolin-5-yl, 2H-isoquinolin-1-on-6-yl,2,4-diaminoquinazolin-7-yl, 4-NH₂-quinazolin-7-yl,

R⁴ is, independently at each occurrence, H, F, Cl, Br, Me, Et, Pr, CN,CF₃, —CH₂OH, —CH₂NH₂, —CO₂H, —C(O)NH₂, —C(O)NHMe, —C(O)N(Me)₂, —CH₂CO₂H,—CH₂C(O)NH₂, or —CH₂CH₂CO₂H; and

R¹¹ is methyl, n-propyl, n-butyl, neopentyl, cyclohexylmethyl,carboxymethyl, benzylaminocarbonylethyl, N-phenethylaminocarbonylethyl,N-benzyl-N-methylaminocarbonylethyl,N-[(pyridine-2-yl)methyl]aminocarbonylethyl,N-[(5-methylpyrazin-2-yl)methyl]aminoethyl,N-(thiazol-2-ylmethyl)aminocarbonylethyl,N-(cyclopropylmethyl)aminocarbonylmethyl, benzyl, phenethyl,2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-chlorobenzyl,3-chlorobenzyl, 4-chlorobenzyl, 2-bromobenzyl, 3-bromobenzyl,4-bromobenzyl, 3-carboxybenzyl, 3-carbamoylbenzyl,3-(N-methylcarbamoyl)-benzyl, 3-(N-ethylcarbamoyl)-benzyl,3-(N,N-dimethylcarbamoyl)-benzyl, 3-tetrazolyl-benzyl, 2-methylbenzyl,3-methylbenzyl, 4-methylbenzyl, 3-trifluoromethylbenzyl,4-trifluoromethylbenzyl, 2-aminobenzyl, 3-aminobenzyl, 2-nitrobenzyl,3-nitrobenzyl, 4-nitrobenzyl, 3-methoxybenzyl, 4-methoxybenzyl,3-difluoromethoxybenzyl, 2-trifluoromethoxybenzyl,3-trifluoromethoxybenzyl, 2-phenoxybenzyl, 3-phenoxybenzyl,2-benzyloxybenzyl, 3-benzyloxybenzyl, 4-benzyloxybenzyl,4-phenylcarbonylbenzyl, 3-methoxycarbonylbenzyl,3-methylcarbonylamino-benzyl, 2-phenylcarbonylamino-benzyl,2-benzylcarbonylamino-benzyl, 3-benzylcarbonylamino-benzyl,3-(benzoyl-methyl-amino)-benzyl, 3-(2-phenylethyl)carbonylamino-benzyl,2-phenylsulfonylamino-benzyl, 3-phenylsulfonylamino-benzyl,3-[N-methyl-N-phenylaminosulfonyl]-benzyl,3-[benzenesulfonyl-methyl-amino]-benzyl, 3-isobutylaminocarbonyl-benzyl,3-t-butylcarbonylamino-benzyl, 3-isopentylaminocarbnoyl-benzyl,3-(2-methylphenyl)carbamoyl-benzyl, 3-(3-methylphenyl)carbamoyl-benzyl,3-(4-methylphenyl)carbamoyl-benzyl, 3-(4-fluorophenyl)carbamoyl-benzyl,3-(1-naphthyl)carbamoyl-benzyl, 3-benzylcarbamoyl-benzyl,3-(4-chlorophenyl)methylcarbamoyl-benzyl,3-(4-methoxyphenyl)methylcarbamoyl-benzyl,3-(2-phenylethyl)carbamoyl-benzyl,3-[2-(4-methoxyphenyl)ethyl]carbamoyl-benzyl,3-[2-(2-chlorophenyl)ethyl]carbamoyl-benzyl,3-[2-(3-chlorophenyl)ethyl]carbamoyl-benzyl,3-[2-(4-chlorophenyl)ethyl]carbamoyl-benzyl,3-[methyl-(pyridin-2-ylethyl)]carbamoyl-benzyl3-(3-phenylpropyl)carbamoyl-benzyl, 3-(ethyl-methyl-carbamoyl)-benzyl,3-(isopropyl-methyl-carbamoyl)-benzyl,3-(isobutyl-methyl-carbamoyl)-benzyl,3-(methyl-phenyl-carbamoyl)-benzyl,3-[(methyl-(3-methylphenyl)-carbamoyl]-benzyl,3-[methyl-(4-methylphenyl)-carbamoyl]-benzyl,3-(benzyl-methyl-carbamoyl)-benzyl,3-[(3-chlorobenzyl)-methyl-carbamoyl]-benzyl,3-[(4-chlorobenzyl)-methyl-carbamoyl]-benzyl,3-[methyl-phenethyl-carbamoyl)]-benzyl,3-(ethyl-phenyl-carbamoyl)-benzyl, 3-(piperidine-1-carbonyl)-benzyl,3-(4-phenyl-piperidine-1-carbonyl)-benzyl,3-(3,4-dihydro-2H-quinoline-1-carbonyl)-benzyl,3-[(2-methoxyethyl)-methyl-carbamoyl]-benzyl,3-(4-methoxy-piperidine-1-carbonyl)-benzyl,3-(morpholine-4-sulfonyl)-benzyl, 3-[(N-(2-methoxyethyl),N-methylamino)sulfonyl]-benzyl, 3-(N,N-dimethylaminosulfonyl)-benzyl,3-(azetidine-1-carbonyl)-benzyl,3-(3-methoxy-azetidine-1-carbonyl)-benzyl,3-(3-hydroxy-pyrrolidine-1-carbonyl)-benzyl,3-[(4-tetrahydropyranyl)methylcarbonyl]-benzyl,3-[(2-hydroxyethyl)-methyl-carbamoyl]-benzyl,3-(3-hydroxy-azetidine-1-carbonyl)-benzyl,3-(4-hydroxypiperidine-1-carbonyl)-benzyl,3-[4-(N,N-dimethylamino)-piperidine-1-carbonyl]-benzyl,3-(4-methyl-piperazine-1-carbonyl)-benzyl,3-[3-(N,N-dimethylamino)-pyrrolidine-1-carbonyl]-benzyl,2-phenyl-benzyl, 3-phenyl-benzyl, 4-phenyl-benzyl, 3-phenethyl-benzyl,benzyloxymethyl, benzylthiomethyl, 1-naphthylmethyl, 2-naphthylmethyl,thiazol-4-ylmethyl, pyrid-2-ylmethyl, pyrid-3-ylmethyl,pyrid-4-ylmethyl, 1-benzyl-imidazol-4-ylmethyl, benzothiazol-2-ylmethyl,3-(1-morpholinocarbonyl)-benzyl,3-[(2,6-dimethylmorpholine-4-carbonyl)-benzyl,(benzyloxycarbonyl)methyl, (1-methylpyrazol-3-yl)methyl,(1-methylpyrazol-4-yl)methyl, (1-methylpyrazol-5-yl)methyl,(3-methylpyrazol-5-yl)methyl, (1-ethylpyrazol-4-yl)methyl,(1-n-propylpyrazol-4-yl)methyl, (1-isopropylpyrazol-4-yl)methyl,1-ethylpyrazol-3-ylmethyl, 3-pyrazolylmethyl,(4-chloro-3-methyl-5-pyrazolyl)methyl,(4-chloro-1,5-dimethyl-3-pyrazolyl)methyl,(4-chloro-1,3-dimethyl-5-pyrazolyl)methyl,[1-(4-methoxybenzyl)-pyrazol-3-yl]methyl,(1,5-dimethylpyrazol-3-yl)methyl, (1,3-dimethylpyrazol-5-yl)methyl,[1-(4-methoxybenzyl)-5-methyl-pyrazol-3-yl]methyl,(3-trifluoromethylpyrazol-5-yl)methyl,[1-(4-methoxybenzyl)-3-trifluoromethylpyrazol-5-yl]methyl,[(1-methyl-5-methoxycarbonyl)-pyrazol-3-yl]methyl,[(1-methyl-5-carboxy)-pyrazol-3-yl]methyl,[(1-methyl-5-carbamoyl)-pyrazol-3-yl]methyl,[(5-methoxycarbonyl)-pyrrol-2-yl]methyl, thiazol-2-ylmethyl,thiazol-4-methyl, (2-methoxypyridin-3-yl)methyl,(6-methoxypyridin-3-yl)methyl, (4-(methoxycarbonyl)-oxazol-2-yl)methyl,morpholin-4-ylcarbonylmethyl,N-((5-methylpyrazin-2-yl)methyl)-aminocarbonylmethyl,2-hydroxy-indan-5-ylmethyl, 4-methylpiperazin-1-ylcarbonylmethyl,4-methylcarbonylpiperazin-1-ylcarbonylmethyl,pyrrolidin-1-ylcarbonylmethyl, 2-methoxypyrrolidin-1-ylcarbonylmethyl,aziridin-1-ylcarbonylmethyl, 2-hydroxyethylaminocarbonylmethyl,2-methoxyethylaminocarbonylmethyl, 2-ethoxyethylaminocarbonylmethyl,bis(2-methoxyethyl)aminocarbonylmethyl,4-dimethylaminopyrrolidin-1-ylcarbonylmethyl,4-chlorophenylaminocarbonylmethyl, 3-chlorophenylcarbonylmethyl,N-methyl-N-benzylaminocarbonylmethyl, cyclopropylaminocarbonylmethyl,cyclopropylmethylaminocarbonylmethyl, cyclopentylaminocarbonylmethyl,(trans-2-phenylcyclopropyl)aminocarbonylmethyl,N,N-dimethylaminoethylaminocarbonylmethyl,N-((pyridin-2-yl)methyl)-aminocarbonylmethyl,N-((pyridin-3-yl)methyl)-aminocarbonylmethyl,N-((pyridin-4-yl)methyl)-aminocarbonylmethyl,N-((pyridin-2-yl)ethyl)-aminocarbonylmethyl,1-(1,1-dioxo-1λ⁶-thiomorpholin-4-yl)carbonylmethyl,N-(tert-butoxycarbonyl)-1H-indol-3-ylmethyl, 1H-indol-3-ylmethyl,2,2-dioxo-2,3-dihydro-1H-2λ⁶-benzo[c]thiophen-5-ylmethyl,4,4,4-trifluorobutyl, cyclopropylmethyl, (4-hydroxy)cyclohexylmethyl,4-oxo-cyclohexylmethyl,

In a sixth aspect, the present invention includes compounds of Formula(I) or its stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, within the scope of any of the first,second, fourth and fifth aspects wherein:

A is 4-aminomethylcyclohexyl, 4-methylcyclohexyl, 4-methoxyphenyl,4-aminomethylphenyl, 4-carbamoylphenyl, 4-amidinophenyl,2-fluoro-4-methylphenyl, 2,6-difluoro-4-methylphenyl,2-fluoro-4-methoxyphenyl, 2,6-difluoro-4-methoxyphenyl,2-fluoro-4-aminomethylphenyl, 2-fluoro-4-carbamoylphenyl,4-amino-2-fluorophenyl, 4-amino-2,6-difluoromethylphenyl,4-amino-3-chloro-2,3-difluorophenyl, 4-amino-3-chlorophenyl,3-chlorothien-2-yl, indol-5-yl, indol-6-yl, indazol-6-yl,3-aminoindazol-6-yl, 3-aminoindazol-5-yl, 1-methyl-3-aminoindazol-6-yl,3-aminobenzisoxazol-6-yl, benzimidazol-5-yl, 6-fluorobenzimidazol-5-yl,1,2,3,4-tetrahydroisoquinolin-6-yl, 1,2,3,4-tetrahydroisoquinolin-3-yl,2H-isoquinolin-1-on-6-yl, isoquinolin-6-yl, 1-amino-isoquinolin-6-yl,1-amino-3-methyl-isoquinolin-6-yl,1-amino-5,6,7,8-tetrahydroisoquinolin-6-yl, 4-amino-quinazolin-7-yl,3H-quinazolin-4-on-7-yl, 3-chlorophenyl, 3-bromophenyl, 3-methylphenyl,3-methoxyphenyl, 2,5-dichlorophenyl, 5-chloro-2-fluorophenyl,5-bromo-2-fluorophenyl, 3-chloro-2-fluorophenyl,2-methyl-5-chlorophenyl, 2-methoxy-5-chlorophenyl,2-methylthio-5-chlorophenyl, 2-ethylthio-5-chlorophenyl,2-propylthio-5-chlorophenyl, 2-benzylthio-5-chlorophenyl,2-amino-5-chlorophenyl, 2-aminomethyl-5-chlorophenyl,2,6-difluoro-3-methylphenyl, 2-chloro-6-fluoro-3-methylphenyl,2-fluoro-6-chloro-3-methylphenyl, 2,6-difluoro-3-chlorophenyl,2,3-dichloro-6-nitrophenyl, 5-chloro-2-thienyl,3,4-methylenedioxyphenyl, 2-methoxycarbonyl-5-chlorophenyl,6-chlorobenzimidazol-4-yl, 2-(3-carboxypyrazol-1-yl)-5-chlorophenyl,2-(1,2,3-triazol-1-yl)-5-methylphenyl,2-(1,2,3-triazol-1-yl)-5-chlorophenyl,2-(1,2,4-triazol-1-yl)-5-chlorophenyl,2-(1,2,3-triazol-2-yl)-5-chlorophenyl,2-[(4-carboxy)-1,2,3-triazol-1-yl]-5-chlorophenyl,2-[(4-carboxy)-1,2,3-triazol-1-yl]-5-methylphenyl,2-[(4-ethoxycarbonyl)-1,2,3-triazol-1-yl]-5-chlorophenyl,2-(tetrazol-1-yl)-5-methyl-phenyl, 2-(tetrazol-1-yl)-5-chlorophenyl,2-(tetrazol-1-yl)-3-fluoro-5-chlorophenyl,2-(tetrazol-1-yl)-3-fluoro-5-methylphenyl, or2-(5-methyltetrazol-1-yl)-5-chlorophenyl;

R³ is, independently at each occurrence,

and

R¹¹ is methyl, n-butyl, cyclohexylmethyl, carboxymethyl, benzyl,phenethyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl,2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 3-carboxybenzyl,3-carbamoylbenzyl, 3-(N-methylcarbamoyl)-benzyl,3-(N,N-dimethylcarbamoyl)-benzyl, 3-(N-ethylcarbamoyl)-benzyl,3-methylbenzyl, 4-methylbenzyl, 3-methoxybenzyl,3-difluoromethoxybenzyl, 3-trifluoromethoxy-benzyl,3-methoxycarbonylbenzyl, 3-methylcarbonylamino-benzyl,3-benzylcarbonylamino-benzyl, 3-(benzoyl-methyl-amino)-benzyl,3-(2-phenylethyl)carbonylamino-benzyl, 2-phenylsulfonylamino-benzyl,3-phenylsulfonylamino-benzyl, 3-[N-methyl,N-phenylaminosulfonyl]-benzyl, 3-(benzenesulfonyl-methyl-amino)-benzyl,3-(2-methylphenyl)carbamoyl-benzyl, 3-(3-methylphenyl)carbamoyl-benzyl,3-(4-methylphenyl)carbamoyl-benzyl, 3-(4-fluorophenyl)carbamoyl-benzyl,3-(1-naphthyl)carbamoyl-benzyl, 3-benzylcarbamoyl-benzyl,3-(4-chlorophenyl)methylcarbamoyl-benzyl,3-(4-methoxyphenyl)methylcarbamoyl-benzyl,3-(2-phenylethyl)carbamoyl-benzyl,3-[2-(4-methoxyphenyl)ethyl]carbamoyl-benzyl,3-[2-(2-chlorophenyl)ethyl]carbamoyl-benzyl,3-[2-(3-chlorophenyl)ethyl]carbamoyl-benzyl,3-[2-(4-chlorophenyl)ethyl]carbamoyl-benzyl,3-[methyl-(pyridin-2-ylethyl)]carbamoyl-benzyl3-(3-phenylpropyl)carbamoyl-benzyl, 3-(ethyl-methyl-carbamoyl)-benzyl,3-(isopropyl-methyl-carbamoyl)-benzyl,3-(isobutyl-methyl-carbamoyl)-benzyl,3-(methyl-phenyl-carbamoyl)-benzyl,3-[(methyl-(3-methylphenyl)-carbamoyl]-benzyl,3-[methyl-(4-methylphenyl)-carbamoyl]-benzyl,3-(benzyl-methyl-carbamoyl)-benzyl,3-[(3-chlorobenzyl)-methyl-carbamoyl]-benzyl,3-[(4-chlorobenzyl)-methyl-carbamoyl]-benzyl,3-[methyl-phenethyl-carbamoyl)]-benzyl,3-(ethyl-phenyl-carbamoyl)-benzyl, 3-(piperidine-1-carbonyl)-benzyl,3-(3,4-dihydro-2H-quinoline-1-carbonyl)-benzyl,3-[(2-methoxyethyl)-methyl-carbamoyl]-benzyl,3-(4-methoxy-piperidine-1-carbonyl)-benzyl,3-(morpholine-4-sulfonyl)-benzyl, 3-[(N-(2-methoxyethyl),N-methylamino)sulfonyl]-benzyl, 3-(N,N-dimethylaminosulfonyl)-benzyl,3-(azetidine-1-carbonyl)-benzyl,3-(3-methoxy-azetidine-1-carbonyl)-benzyl,3-(3-hydroxy-pyrrolidine-1-carbonyl)-benzyl,3-[(4-tetrahydropyranyl)methylcarbonyl]-benzyl,3-[(2-hydroxyethyl)-methyl-carbamoyl]-benzyl,3-(3-hydroxy-azetidine-1-carbonyl)-benzyl,3-(4-hydroxypiperidine-1-carbonyl)-benzyl,3-[4-(N,N-dimethylamino)-piperidine-1-carbonyl]-benzyl,3-(4-methyl-piperazine-1-carbonyl)-benzyl,3-[3-(N,N-dimethylamino)-pyrrolidine-1-carbonyl]-benzyl,1-naphthylmethyl, 2-naphthylmethyl, thiazol-4-ylmethyl,pyrid-2-ylmethyl, pyrid-3-ylmethyl, pyrid-4-ylmethyl,1-benzyl-imidazol-4-ylmethyl, benzothiazol-2-ylmethyl,3-(1-morpholinocarbonyl)-benzyl,3-[(2,6-dimethylmorpholine-1-carbonyl)-benzyl,(benzyloxycarbonyl)methyl, (1-methylpyrazol-3-yl)methyl,(1-methylpyrazol-4-yl)methyl, (1-methylpyrazol-5-yl)methyl,(3-methylpyrazol-5-yl)methyl, (1-ethylpyrazol-4-yl)methyl,(1-n-propylpyrazol-4-yl)methyl, (1-isopropylpyrazol-4-yl)methyl,1-ethylpyrazol-3-ylmethyl, 3-pyrazolylmethyl,(4-chloro-3-methyl-5-pyrazolyl)methyl,(4-chloro-1,5-dimethyl-3-pyrazolyl)methyl,(4-chloro-1,3-dimethyl-5-pyrazolyl)methyl,[1-(4-methoxybenzyl)-pyrazol-3-yl]methyl,(1,5-dimethylpyrazol-3-yl)methyl, (1,3-dimethylpyrazol-5-yl)methyl,[1-(4-methoxybenzyl)-5-methyl-pyrazol-3-yl]methyl,(3-trifluoromethylpyrazol-5-yl)methyl,[1-(4-methoxybenzyl)-3-trifluoromethylpyrazol-5-yl]methyl,[(1-methyl-5-methoxycarbonyl)-pyrazol-3-yl]methyl,[(1-methyl-5-carboxy)-pyrazol-3-yl]methyl,[(1-methyl-5-carbamoyl)-pyrazol-3-yl]methyl,[(5-methoxycarbonyl)-pyrrol-2-yl]methyl, thiazol-2-ylmethyl,thiazol-4-methyl, (2-methoxypyridin-3-yl)methyl,(6-methoxypyridin-3-yl)methyl, (4-(methoxycarbonyl)-oxazol-2-yl)methyl,morpholin-4-ylcarbonylmethyl,N-((5-methylpyrazin-2-yl)methyl)-aminocarbonylmethyl,2-hydroxy-indan-5-ylmethyl, 4-methylpiperazin-1-ylcarbonylmethyl,4-methylcarbonylpiperazin-1-ylcarbonylmethyl,pyrrolidin-1-ylcarbonylmethyl, 2-methoxypyrrolidin-1-ylcarbonylmethyl,aziridin-1-ylcarbonylmethyl, 2-hydroxyethylaminocarbonylmethyl,2-methoxyethylaminocarbonylmethyl, 2-ethoxyethylaminocarbonylmethyl,bis(2-methoxyethyl)aminocarbonylmethyl,4-dimethylaminopyrrolidin-1-ylcarbonylmethyl,4-chlorophenylaminocarbonylmethyl, 3-chlorophenylcarbonylmethyl,N-methyl-N-benzylaminocarbonylmethyl, cyclopropylaminocarbonylmethyl,cyclopropylmethylaminocarbonylmethyl, cyclopentylaminocarbonylmethyl,(trans-2-phenylcyclopropyl)aminocarbonylmethyl,N,N-dimethylaminoethylaminocarbonylmethyl,N-((pyridin-2-yl)methyl)-aminocarbonylmethyl,N-((pyridin-3-yl)methyl)-aminocarbonylmethyl,N-((pyridin-4-yl)methyl)-aminocarbonylmethyl,N-((pyridin-2-yl)ethyl)-aminocarbonylmethyl,1-(1,1-dioxo-1λ⁶-thiomorpholin-4-yl)carbonylmethyl,N-(tert-butoxycarbonyl)-1H-indol-3-ylmethyl, 1H-indol-3-ylmethyl,2,2-dioxo-2,3-dihydro-1H-2λ⁶-benzo[c]thiophen-5-ylmethyl,4,4,4-trifluorobutyl, cyclopropylmethyl, (4-hydroxy)cyclohexylmethyl,4-oxo-cyclohexylmethyl,

In a seventh aspect, the present invention includes compounds of Formula(I) stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, within the scope of the first aspectwherein:

A is 4-aminomethyl-cyclohexyl, 2,6-difluoro-4-methoxyphenyl, or2-(tetrazol-1-yl)-5-chlorophenyl;

L₁ is a bond or —CH═CH—;

R⁴ is H or Cl;

R³ is 3-carboxy-phenyl, 4-carboxy-phenyl, 4-carbamoyl-phenyl,4-methoxycarbonylamino-phenyl, or 3-amino-indazol-6-yl; and

R¹¹ is benzyl.

In a seventh aspect, the present invention provides a compound selectedfrom the exemplified examples or stereoisomers, tautomers,pharmaceutically acceptable salts, solvates, or prodrugs thereof.

In another aspect, the present invention provides, inter alia, compoundsof Formula (II):

or stereoisomers, tautomers, pharmaceutically acceptable salts,solvates, or prodrugs thereof, wherein:

A is substituted with 0-1 R¹ and 0-3 R² and is selected from the group:C₃₋₇ cycloalkyl, C₃₋₇ cycloalkenyl, phenyl, naphthyl, or a 5- to10-membered heterocycle comprising: carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p);

optionally, the thiophene ring is further substituted with 0-2 R⁴;

Z is —CHR¹¹—;

L is —(CH₂)_(r)C(O)NR¹⁰—, —CH═CHC(O)NR¹⁰—, —C≡CC(O)NR¹⁰—,—OCH₂C(O)NR¹⁰—, —CH₂OC(O)NR¹⁰—, —SCH₂C(O)NR¹⁰—, —SO₂CH₂C(O)NR¹⁰—,—CH₂NHC(O)NR¹⁰—, —NHNHC(O)NH—, —(CH₂)_(r)NR¹⁰C(O)—,—(CH₂)_(r)NR¹⁰C(O)NR¹⁰—, —SCH₂NHC(O)—, —OCH₂NHC(O)—, or; provided thatwhen L is —SCH₂NHC(O)—, —OCH₂NHC(O)—, or —NHNHC(O)NH— then Z is otherthan NR¹²;

R¹ is, independently at each occurrence, H, —NH₂, —NH(C₁₋₃ alkyl),—(CH₂)_(r)NR⁷R⁸, —(CH₂)_(r)NR⁷C(O)OR⁹, —CH(C₁₋₄ alkyl)NH₂, —CH(C₁₋₄alkyl)₂NH₂, —N(C₁₋₃ alkyl)₂, —C(═NH)NH₂, —C(O)NH₂, —CH₂NH₂, —CH₂NH(C₁₋₃alkyl), —CH₂N(C₁₋₃ alkyl)₂, —CH₂CH₂NH₂, —CH₂CH₂NH(C₁₋₃ alkyl),—CH₂CH₂N(C₁₋₃ alkyl)₂, —C(═NR^(8a))NR⁸R⁹, —NR⁸CR⁸(═NR^(8a)), —NR⁷R⁸,—C(O)NR⁷R⁸, —S(O)_(p)NR⁸R⁹, F, Cl, Br, I, OCF₃, CF₃, OR^(a), SR^(a), CNor C₁₋₆ alkyl substituted with 0-1 R^(1a);

R^(1a) is —C(═NR^(8a))NR⁸R⁹, —NHC(═NR^(8a))NR⁸R⁹, —NR⁸CH(═NR^(8a)),—ONHC(═NR^(8a))NR⁸R⁹, —NR⁷R⁸, —C(O)NR⁷R⁸, F, OCF₃, CF₃, OR^(a), SR^(a),CN, —NR⁸SO₂NR⁸R⁹, —NR⁸SO₂R^(c), or —(CF₂)_(r)CF₃;

R² is, independently at each occurrence, H, ═O, F, Cl, Br, CF₃, OCF₃,CHF₂, CN, NO₂, OR^(a), SR^(a), —C(O)R^(a), —C(O)OR^(a), —OC(O)R^(a),—NR⁷R⁸, —C(O)NR⁸R⁹, —NR⁸C(O)R^(c), —NR⁸C(O)OR^(c), —NR⁸C(O)NR⁸R^(c),—S(O)_(p)NR⁸R⁹, —NR⁸S(O)_(p)R^(c), —S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkylsubstituted with 0-2 R^(2a), C₂₋₆ alkenyl substituted with 0-2 R^(2a),C₂₋₆ alkynyl substituted with 0-2 R^(2a), C₃₋₇ cycloalkyl substitutedwith 0-2 R^(2a), —(CH₂)_(r)-phenyl substituted with 0-2 R^(2b), or—(CH₂)_(r)-5- to 6-membered heterocycle comprising: carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), wherein said heterocycleis substituted with 0-3 R^(2b);

R^(2a) is, independently at each occurrence, H, F, Cl, Br, I, ═O, ═NR⁸,CN, OCF₃, CF₃, OR^(a), SR^(a), —NR⁷R⁸, —C(O)NR⁸R⁹, —NR⁸C(O)R^(c),—NR⁸C(O)OR^(c), —NR⁸C(O)NR⁸R^(c), —S(O)_(p)NR⁸R⁹, —NR⁸SO₂R^(c),—S(O)R^(c), or —S(O)₂R^(c);

R^(2b) is, independently at each occurrence, H, F, Cl, Br, I, ═O, ═NR⁸,—(CH₂)_(r)CN, —(CH₂)_(r)NO₂, —(CH₂)_(r)OR^(a), —(CH₂)_(r)SR^(a),—(CH₂)_(r)C(O)R^(a), —(CH₂)_(r)C(O)OR^(a), —(CH₂)_(r)OC(O)R^(a),—(CH₂)_(r)NR⁷R⁸, —(CH₂)_(r)C(O)NR⁸R⁹, —(CH₂)_(r)NR⁸C(O)R^(c),—(CH₂)_(r)S(O)_(p)NR⁸R⁹, —(CH₂)_(r)SO₂R^(c), —(CH₂)_(r)NR⁸SO₂NR⁸R⁹,—(CH₂)_(r)NR⁸SO₂R^(c), —(CF₂)_(r)CF₃, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, C₁₋₄ haloalkyl, or C₁₋₄ haloalkyloxy;

alternately, when R¹ and R² are substituted on adjacent ring atoms, theycan be taken together with the ring atoms to which they are attached toform a 5- to 7-membered carbocycle or heterocycle comprising: carbonatoms and 0-4 heteroatoms selected from N, O, and S(O)_(p), wherein saidcarbocycle or heterocycle is substituted with 0-2 R^(2b);

R³ is phenyl substituted with 0-3 R^(3a) and 0-1 R^(3d), naphthylsubstituted with 0-3 R^(3a) and 0-1 R^(3d), or —(CH₂)_(r)-5- to12-membered heterocycle comprising: carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p), wherein said heterocycle issubstituted with 0-3 R^(3a) and 0-1 R^(3d);

R^(3a) is, independently at each occurrence, ═O, ═NR⁸, F, Cl, Br, I,OCF₃, CF₃, —(CH₂)_(r)CN, NO₂, —(CH₂)_(r)OR^(3b), —(CH₂)_(r)—SR^(3b),—(CH₂)_(r)NR⁷R⁸, —C(═NR^(8a))NR⁸R⁹, —NHC(═NR^(8a))NR⁸R⁹, —C(O)OR^(3b),—C(O)C₁₋₄ alkyl, —SO₂NHR^(3b), —SO₂NHCOR^(3c), —SO₂NHCO₂R^(3c),—CONHSO₂R^(3c), —NR⁸CR⁸(═NR^(8a)), —NHC(O)NR⁸R⁹,—(CH₂)_(r)NR⁸C(O)R^(3b), —(CH₂)_(r)NR⁸CO₂R^(3b),—(CH₂)_(r)S(O)_(p)NR⁸R⁹, —(CH₂)_(r)NR⁸S(O)_(p)R^(3c), —NHSO₂CF₃,—S(O)R^(3c), —S(O)₂R^(3c), —(CH₂)_(r)CO₂R^(3b), —(CH₂)_(r)C(O)NR⁸R⁹,—(CH₂)_(r)OC(O)NR⁸R⁹, —NHCOCF₃, —NHSO₂R^(3c), —CONHOR^(3b), C₁₋₄haloalkyl, C₁₋₄ haloalkyloxy, C₁₋₆ alkyl substituted by R^(3e), C₂₋₆alkenyl substituted by R^(3e), C₁₋₆ alkynyl substituted by R^(3e), C₃₋₆cycloalkyl substituted by 0-1 R^(3d), —(CH₂)_(r)—C₆₋₁₀ carbocyclesubstituted by 0-3 R^(3d) or —(CH₂)_(r)-5- to 10-membered heterocyclecomprising: carbon atoms and 1-4 heteroatoms selected from N, O, andS(O)_(p), wherein said heterocycle is substituted with 0-3 R^(3d);

alternately, when two R^(3a) groups are substituted on adjacent atoms,they can be taken together with the atoms to which they are attached toform a C₃₋₁₀ carbocycle substituted with 0-2 R^(3d), or a 5- to10-membered heterocycle comprising: carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p), wherein said heterocycle issubstituted with 0-2 R^(3d);

R^(3b) is, independently at each occurrence, H, C₁₋₆ alkyl substitutedwith 0-2 R^(3e), C₂₋₆ alkenyl substituted with 0-2 R^(3e), C₂₋₆ alkynylsubstituted with 0-2 R^(3e), —(CH₂)_(r)—C₃₋₁₀ carbocycle substitutedwith 0-3 R^(3d), or —(CH₂)_(r)-5- to 10-membered heterocycle comprising:carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p),wherein said heterocycle is substituted with 0-3 R^(3d);

R^(3c) is, independently at each occurrence, C₁₋₆ alkyl substituted with0-2 R^(3d), C₂₋₆ alkenyl substituted with 0-2 R^(3d), C₂₋₆ alkynylsubstituted with 0-2 R^(3d), —(CH₂)_(r)—C₃₋₁₀ carbocycle substitutedwith 0-3 R^(3d), or —(CH₂)_(r)-5- to 10-membered heterocycle comprising:carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p),wherein said heterocycle is substituted with 0-3 R^(3d);

R^(3d) is, independently at each occurrence, H, ═O, F, Cl, Br, CN, NO₂,—(CH₂)_(r)NR⁷R⁸, —(CH₂)_(r)OR^(a), —C(O)R^(a), —C(O)OR^(a), —OC(O)R^(a),—NR⁸C(O)R^(c), —C(O)NR⁸R⁹, —S(O)₂NR⁸R⁹, —NR⁷R⁸, —NR⁸S(O)₂NR⁸R⁹,—NR⁸S(O)₂R^(c), —S(O)_(p)R^(c), —(CF₂)_(r)CF₃, C₁₋₆ alkyl substitutedwith 0-2 R^(e), C₂₋₆ alkenyl substituted with 0-2 R^(e), C₂₋₆ alkynylsubstituted with 0-2 R^(e), —(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with0-3 R^(d), or —(CH₂)_(r)-5- to 10-membered heterocycle comprising:carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p),wherein said heterocycle is substituted with 0-3 R^(d);

R^(3e) is, independently at each occurrence, H, —(CH₂)_(r)OR^(a), F, ═O,CN, NO₂, —(CH₂)_(r)NR⁷R⁸, —C(O)R^(a), —C(O)OR^(a), —OC(O)R^(a),—NR⁸C(O)R^(c), —C(O)NR⁸R⁹, —S(O)₂NR⁸R⁹, —NR⁸S(O)₂NR⁸R⁹, —NR⁸S(O)₂R^(c),—S(O)_(p)R^(c), —(CF₂)_(r)CF₃, —(CH₂)_(r)—C₃₋₁₀ carbocycle substitutedwith 0-3 R^(d), or —(CH₂)_(r)-5- to 10-membered heterocycle comprising:carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p),wherein said heterocycle is substituted with 0-3 R^(d);

R⁴ is, independently at each occurrence, H, F, Cl, Br, I, CF₃, CN, NO₂,—(CH₂)_(r)OR^(a), —(CH₂)_(r)SR^(a), —(CH₂)_(r)C(O)R^(a),—(CH₂)_(r)C(O)OR^(a), —(CH₂)_(r)NR⁷R⁸, —(CH₂)_(r)C(O)NR⁸R⁹,—(CH₂)_(r)NR⁸C(O)R^(c), —(CH₂)_(r)NR⁸C(O)₂R^(b), —(CH₂)_(r)NR⁸C(O)NR⁸R⁹,C₁₋₆ alkyl substituted with 0-2 R^(4a), C₂₋₆ alkenyl substituted with0-2 R^(4a), C₂₋₆ alkynyl substituted with 0-2 R^(4a), —(CH₂)_(r)—C₃₋₁₀carbocycle substituted with 0-3 R^(4b), or —(CH₂)_(r)-5- to 10-memberedheterocycle comprising: carbon atoms and 1-4 heteroatoms selected fromN, O, and S(O)_(p), wherein said heterocycle is substituted with 0-3R^(4b);

R^(4a) is, independently at each occurrence, H, F, ═O, C₁₋₄ alkyl,OR^(a), SR^(a), CF₃, CN, NO₂, —C(O)R^(a), —C(O)OR^(a), —NR⁷R⁸,—C(O)NR⁸R⁹, —NR⁷C(O)R^(c), —S(O)_(p)NR⁸R⁹, —NR⁸S(O)_(p)R^(c),—S(O)R^(c), or —S(O)₂R^(c);

R^(4b) is, independently at each occurrence, H, ═O, ═NR⁸, OR^(a),SR^(a), F, Cl, Br, I, CN, NO₂, —NR⁷R⁸, —C(O)R^(a), —C(O)OR^(a),—NR⁷C(O)R^(c), —C(O)NR⁸R⁹, —SO₂NR⁸R⁹, —S(O)₂R^(c), C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₁₋₄ haloalkyl, or C₁₋₄haloalkyloxy;

R⁷ is, independently at each occurrence, H, C₁₋₆ alkyl, —(CH₂)_(n)—C₃₋₁₀carbocycle, —(CH₂)_(n)-(5- to 10-membered heteroaryl), —C(O)R^(c), —CHO,—C(O)₂R^(c), —S(O)₂R^(c), —CONR⁸R^(c), —OCONHR^(c), —C(O)O—(C₁₋₄alkyl)OC(O)—(C₁₋₄ alkyl), or —C(O)O—(C₁₋₄ alkyl)OC(O)—(C₆₋₁₀ aryl);wherein said alkyl, carbocycle, heteroaryl, and aryl are substitutedwith 0-2 R^(f); wherein said heteroaryl comprises: carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p);

R⁸ is, independently at each occurrence, H, C₁₋₆ alkyl,—(CH₂)_(n)-phenyl, or —(CH₂)_(n)-5-10 membered heterocycle comprising:carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p);wherein said alkyl, phenyl and heterocycle are optionally substitutedwith 0-2 R^(f);

alternatively, R⁷ and R⁸, when attached to the same nitrogen, combine toform a 5- to 10-membered heterocycle comprising: carbon atoms and 0-3additional heteroatoms selected from N, O, and S(O)_(p), wherein saidheterocycle is substituted with 0-2 R^(f);

R^(8a) is, independently at each occurrence, R⁷, OH, C₁₋₄ alkoxy, (C₆₋₁₀aryl)-C₁₋₄ alkoxy; wherein said aryl is optionally substituted with 0-2R^(f);

R⁹ is, independently at each occurrence, H, C₁₋₆ alkyl, or—(CH₂)_(n)-phenyl; wherein said alkyl and phenyl are optionallysubstituted with 0-2 R^(f);

alternatively, R⁸ and R⁹, when attached to the same nitrogen, combine toform a 5- to 12-membered heterocycle comprising: carbon atoms and 0-2additional heteroatoms selected from N, O, and S(O)_(p), wherein saidheterocycle is substituted with 0-2 R^(d);

R¹⁰ is, independently at each occurrence, H, C₁₋₆ alkyl substituted with0-2 R^(10a), —(CH₂)_(r)-phenyl substituted with 0-3 R^(d), or—(CH₂)_(r)-5- to 10-membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), and substituted with 0-3R^(d);

R^(10a) is, independently at each occurrence, H, ═O, C₁₋₄ alkyl, OR^(a),SR², F, CF₃, CN, NO₂, —C(O)R^(a), —C(O)OR^(a), —C(O)NR⁷R⁸,—NR⁷C(O)R^(b), —S(O)_(p)NR⁸R⁹, —NR⁸S(O)_(p)R^(c), or —S(O)_(p)R^(c);

R¹¹ is C₁₋₄ haloalkyl, —C(O)NR⁸R⁹, —CH₂C(O)NR⁸R⁹, —CH₂CH₂C(O)NR⁸R⁹,—C(O)R^(a), —CH₂C(O)R^(a), —CH₂CH₂C(O)R^(a), —C(O)OR^(a),—CH₂C(O)OR^(a), —CH₂CH₂C(O)OR^(a), C₁₋₆ alkyl substituted with 0-3R^(11c), C₂₋₆ alkenyl substituted with 0-3 R^(11a); C₂₋₆ alkynylsubstituted with 0-3 R^(11a), —(CH₂)_(s)—C₃₋₇ cycloalkyl substitutedwith 0-2 R^(11b), —(CH₂)_(s)-phenyl substituted with 0-3 R^(11b),—(CH₂)_(s)-naphthyl substituted with 0-3 R^(11b), or —(CH₂)_(s)-5- to10-membered heterocycle comprising: carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p), wherein said heterocycle issubstituted with 0-3 R^(11b);

R^(11a) is, independently at each occurrence, H, ═O, C₁₋₄ alkyl, OR^(a),SR^(a), F, CF₃, CN, NO₂, —NR⁷R⁸, —C(O)R^(a), —C(O)OR^(a), —C(O)NR⁸R⁹,—NR⁸C(O)R^(c), —NR⁸C(O)OR^(c), —NR⁸CHO, —S(O)_(p)NR⁸R⁹,—NR⁸S(O)_(p)R^(c), —S(O)_(p)R^(c), C₃₋₆ cycloalkyl, C₁₋₄ haloalkyl, C₁₋₄haloalkyloxy, —(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(d), or—(CH₂)_(r)-5- to 10-membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), and substituted with 0-3R^(d);

R^(11b) is, independently at each occurrence, H, ═O, ═NR⁸, OR^(a),SR^(a), F, Cl, Br, CN, NO₂, CF₃, OCF₃, OCHF₂, —NR⁷R⁸, —C(O)R^(a),—C(O)OR^(a), —C(O)NR⁸R⁹, —NR⁸C(O)R^(c), —NR⁸C(O)₂R^(c), —S(O)_(p)NR⁸R⁹,—NR⁸S(O)_(p)R^(c), —S(O)_(p)R^(c), C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, C₃₋₆ cycloalkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkyloxy,—(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(d), or —(CH₂)_(r)-5-to 10-membered heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p), and substituted with 0-3 R^(d);

alternately, when two R^(11b) groups are substituents on adjacent atomsthey may be taken together with the atoms to which they are attached toform a 5- to 7-membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p) and substituted with 0-2R^(g);

R^(11c) is, independently at each occurrence H, ═O, OR^(a), SR^(a), F,CF₃, CN, NO₂, —NR⁷R⁸, —NR⁸C(O)R^(c), —NR⁸C(O)OR^(c), —NR⁸CHO,—S(O)_(p)NR⁸R⁹, —NR⁸S(O)_(p)R^(c), —S(O)_(p)R^(c), C₁₋₄ alkyl, C₃₋₆cycloalkyl, C₁₋₄ haloalkyl, C₁₋₄ haloalkyloxy, —(CH₂)_(r)—C₃₋₁₀carbocycle substituted with 0-3 R^(d), or —(CH₂)_(r)-5- to 10-memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,O, and S(O)_(p), and substituted with 0-3 R^(d);

R¹² is C₁₋₆ alkyl, —(CH₂)_(s)-cycloalkyl, —(CH₂)_(s)-phenyl,—(CH₂)_(s)-naphthyl, —(CH₂)_(r)NR⁸C(O)R^(a), —C(O)R^(c), —C(O)OR^(c),—CONR⁸R^(c), —S(O)₂R^(c), —C(O)O—(C₁₋₄ alkyl)-OC(O)—(C₁₋₄ alkyl),—C(O)O—(C₁₋₄ alkyl)-OC(O)—(C₆₋₁₀ aryl), or —(CH₂)_(s)-5- to 10-memberedheteroaryl comprising: carbon atoms and 1-4 heteroatoms selected from N,O, and S(O)_(p); wherein said alkyl, phenyl, aryl, and heteroaryl areoptionally substituted with 0-3 R^(f);

R^(a) is, independently at each occurrence, H, CF₃, C₁₋₆ alkyl,—(CH₂)_(r)—C₃₋₇ cycloalkyl, —(CH₂)_(r)—C₆₋₁₀ aryl, or —(CH₂)_(r)-5- to10-membered heteroaryl comprising carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p); wherein said cycloalkyl, aryl orheteroaryl groups are optionally substituted with 0-2 R^(f);

R^(b) is, independently at each occurrence, CF₃, OH, C₁₋₄ alkoxy, C₁₋₆alkyl, —(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(d), or—(CH₂)_(r)-5- to 10-membered heterocycle comprising: carbon atoms and1-4 heteroatoms selected from N, O, and S(O)_(p) and substituted with0-3 R^(d);

R^(c) is, independently at each occurrence, CF₃, C₁₋₆ alkyl substitutedwith 0-2 R^(f), C₃₋₆ cycloalkyl substituted with 0-2 R^(f), C₆₋₁₀ aryl,5- to 10-membered heteroaryl, (C₆₋₁₀ aryl)-C₁₋₄ alkyl, or (5- to10-membered heteroaryl)-C₁₋₄ alkyl, wherein said aryl is substitutedwith 0-3 R^(f) and said heteroaryl comprises: carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p) and substituted with 0-3R^(f);

R^(d) is, independently at each occurrence, H, ═O, ═NR⁸, OR^(a), F, Cl,Br, I, CN, NO₂, —NR⁷R⁸, —C(O)R^(a), —C(O)OR^(a), —OC(O)R^(a),—NR⁸C(O)R^(c), —C(O)NR⁸R⁹, —SO₂NR⁸R⁹, —NR⁸SO₂NR⁸R⁹, —NR⁸SO₂—C₁₋₄ alkyl,—NR⁸SO₂CF₃, —NR⁸SO₂-phenyl, —S(O)₂CF₃, —S(O)_(p)—C₁₋₄ alkyl,—S(O)_(p)-phenyl, —(CF₂)_(r)CF₃, C₁₋₆ alkyl substituted with 0-2 R^(e),C₂₋₆ alkenyl substituted with 0-2 R^(e), or C₂₋₆ alkynyl substitutedwith 0-2 R^(e);

R^(e) is, independently at each occurrence, ═O, OR^(a), F, Cl, Br, I,CN, NO₂, —NR⁷R⁸, —C(O)R^(a), —C(O)OR^(a), —NR⁸C(O)R^(c), —C(O)NR⁸R⁹,—SO₂NR⁸R⁹, —NR⁸SO₂NR⁸R⁹, —NR⁸SO₂—C₁₋₄ alkyl, —NR⁸SO₂CF₃, —NR⁸SO₂-phenyl,—S(O)₂CF₃, —S(O)_(p)—C₁₋₄ alkyl, —S(O)_(p)-phenyl, or —(CF₂)_(r)CF₃;

R^(f) is, independently at each occurrence, H, ═O, —(CH₂)_(r)OR^(g), F,Cl, Br, I, CN, NO₂, —NR^(g)R^(g), —C(O)R9, —C(O)OR^(g),—NR^(g)C(O)R^(g), —C(O)NR^(g)R^(g), —SO₂NR^(g)R^(g),—NR^(g)SO₂NR^(g)R^(g), —NR^(g)SO₂—C₁₋₄ alkyl, —NR^(g)SO₂CF₃,—NR^(g)SO₂-phenyl, —S(O)₂CF₃, —S(O)_(p)—C₁₋₄ alkyl, —S(O)_(p)-phenyl,—(CH₂)_(n)-phenyl, —(CF₂)_(r)CF₃, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, —(CH₂)_(n)-phenyl, or —(CH₂)_(n)-5- to 10-membered heterocyclecomprising carbon atoms and 1-4 heteroatoms selected from N, O, andS(O)_(p);

alternately, when two R^(f) groups are substituents on adjacent atomsthey may be taken together with the atoms to which they are attached toform a 5-7-membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p) and substituted with 0-2R^(g);

R^(g) is, independently at each occurrence, H, C₁₋₆ alkyl, or—(CH₂)_(X)-phenyl;

n, at each occurrence, is selected from 0, 1, 2, 3, and 4;

p, at each occurrence, is selected from 0, 1, and 2; and

r, at each occurrence, is selected from 0, 1, 2, 3, and 4; and

s, at each occurrence, is selected from 1, 2, 3, and 4;

provided that: when R¹¹ is —CH₂CO₂H, L₁ is other than —CH₂O—;(778606-28-3, 777937-24-3)

In another embodiment, A is substituted with 0-1 R¹ and 0-3 R² andselected from; C₃₋₇ cycloalkyl, phenyl, naphthyl, pyridyl,1,2,3,4-tetrahydronaphthyl, pyrrolidinyl, indazolyl, indolyl,imidazolyl, furanyl, thienyl, benzimidazolyl, benzisoxazolyl,benzothiazolyl, benzothiophenyl, 3,4-methylenedioxy-phenyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, quinolinyl,isoquinolinyl, 1H-4-oxo-isoquinazolinyl, 2H-1-oxo-isoquinolinyl,3H-4-oxo-quinazolinyl, 3,4-dihydro-2H-1-oxo-isoquinolinyl,2,3-dihydro-isoindolinyl, 5,6,7,8-tetrahydroquinolinyl,1,2,3,4-tetrahydroquinolinyl, 5,6,7,8-tetrahydroisoquinolinyl,1,2,3,4-tetrahydroisoquinolinyl, quinazolinyl, and phthalazinyl.

In another embodiment, A is 4-aminomethylcyclohexyl, 4-methylcyclohexyl,4-methoxyphenyl, 4-aminomethylphenyl, 4-carbamoylphenyl,4-amidinophenyl, 2-fluoro-4-methylphenyl, 2,6-difluoro-4-methylphenyl,2-fluoro-4-methoxyphenyl, 2,6-difluoro-4-methoxyphenyl,2-fluoro-4-aminomethylphenyl, 2-fluoro-4-carbamoylphenyl,4-amino-2-fluorophenyl, 4-amino-2,6-difluoromethylphenyl,4-amino-3-chloro-2,3-difluorophenyl, 4-amino-3-chlorophenyl,3-chlorothien-2-yl, indol-5-yl, indol-6-yl, indazol-6-yl,3-aminoindazol-6-yl, 3-aminoindazol-5-yl, 1-methyl-3-aminoindazol-6-yl,3-aminobenzisoxazol-6-yl, benzimidazol-5-yl, 6-fluorobenzimidazol-5-yl,1,2,3,4-tetrahydroisoquinolin-6-yl, 1,2,3,4-tetrahydroisoquinolin-3-yl,2H-isoquinolin-1-on-6-yl, isoquinolin-6-yl, 1-amino-isoquinolin-6-yl,1-amino-3-methyl-isoquinolin-6-yl,1-amino-5,6,7,8-tetrahydroisoquinolin-6-yl, 4-amino-quinazolin-7-yl,3H-quinazolin-4-on-7-yl, 3-chlorophenyl, 3-bromophenyl, 3-methylphenyl,3-methoxyphenyl, 2,5-dichlorophenyl, 5-chloro-2-fluorophenyl,5-bromo-2-fluorophenyl, 3-chloro-2-fluorophenyl,2-methyl-5-chlorophenyl, 2-methoxy-5-chlorophenyl,2-methylthio-5-chlorophenyl, 2-ethylthio-5-chlorophenyl,2-propylthio-5-chlorophenyl, 2-benzylthio-5-chlorophenyl,2-amino-5-chlorophenyl, 2-aminomethyl-5-chlorophenyl,2,6-difluoro-3-methylphenyl, 2-chloro-6-fluoro-3-methylphenyl,2-fluoro-6-chloro-3-methylphenyl, 2,6-difluoro-3-chlorophenyl,2,3-dichloro-6-nitrophenyl, 5-chloro-2-thienyl,3,4-methylenedioxyphenyl, 2-methoxycarbonyl-5-chlorophenyl,6-chlorobenzimidazol-4-yl, 2-(3-carboxypyrazol-1-yl)-5-chlorophenyl,2-(1,2,3-triazol-1-yl)-5-methylphenyl,2-(1,2,3-triazol-1-yl)-5-chlorophenyl,2-(1,2,4-triazol-1-yl)-5-chlorophenyl,2-(1,2,3-triazol-2-yl)-5-chlorophenyl,2-[(4-carboxy)-1,2,3-triazol-1-yl]-5-chlorophenyl,2-[(4-carboxy)-1,2,3-triazol-1-yl]-5-methylphenyl,2-[(4-ethoxycarbonyl)-1,2,3-triazol-1-yl]-5-chlorophenyl,2-(tetrazol-1-yl)-5-methyl-phenyl, 2-(tetrazol-1-yl)-5-chlorophenyl,2-(tetrazol-1-yl)-3-fluoro-5-chlorophenyl,2-(tetrazol-1-yl)-3-fluoro-5-methylphenyl, or2-(5-methyltetrazol-1-yl)-5-chlorophenyl.

In another embodiment, A is substituted with 0-1 R¹ and 0-3 R² andselected from; C₃₋₇ cycloalkyl, phenyl, naphthyl, pyridyl,1,2,3,4-tetrahydronaphthyl, pyrrolidinyl, indazolyl, indolyl,imidazolyl, furanyl, thienyl, benzimidazolyl, benzisoxazolyl,benzothiazolyl, benzothiophenyl, 3,4-methylenedioxy-phenyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, quinolinyl,isoquinolinyl, 1H-4-oxo-isoquinazolinyl, 2H-1-oxo-isoquinolinyl,3H-4-oxo-quinazolinyl, 3,4-dihydro-2H-1-oxo-isoquinolinyl,2,3-dihydro-isoindolinyl, 5,6,7,8-tetrahydroquinolinyl,1,2,3,4-tetrahydroquinolinyl, 5,6,7,8-tetrahydroisoquinolinyl,1,2,3,4-tetrahydroisoquinolinyl, quinazolinyl, and phthalazinyl.

In another embodiment, R¹ is, independently at each occurrence, F, Cl,Br, I, OCF₃, CF₃, OCH₃, CH₃, Et, NH₂, —C(═NH)NH₂, —C(O)NH₂, —CH₂NH₂ or—SO₂NH₂.

In another embodiment, R² is, independently at each occurrence, F, Cl,Br, CF₃, NO₂, —(CH₂)_(r)OR^(a), —(CH₂)_(r)SR^(a), —C(O)OR^(a),—C(O)NR⁸R⁹, —NR⁸C(O)R^(c), —NR⁸C(O)OR^(c), —NR⁸C(O)NR⁸R^(c),—S(O)_(p)NR⁸R⁹, —NR⁸SO₂R^(c), —NR⁷R⁸, —S(O)R^(c), —S(O)₂R^(c), C₁₋₆alkyl substituted with 0-1 R²², or a 5-7 membered heterocycle comprisingcarbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p),wherein said heterocycle is substituted with 0-2 R^(2b).

In another embodiment, R² is, independently at each occurrence, ═O, F,Cl, Br, CF₃, Me, Et, OR^(a), CN, NO₂, NR⁷R⁸, —CH₂OMe, —SR^(a), —CH₂SMe,—C(O)OR^(a), —CH₂NR⁷R⁸, —SO₂NH₂, —SO₂Me, —NHSO₂R^(c), —CH₂NHSO₂R^(c),—C(O)NR⁸R⁹, —NHC(O)R^(c), —CH₂NHC(O)R^(c), —NHC(O)OR^(c),—CH₂NHC(O)OR^(c), —NHC(O)NHR^(c), —CH₂NHC(O)NHR^(c), or a 5-7 memberedheterocycle substituted with 0-2 R^(2b) and selected from: pyrrolidinyl,2-oxo-1-pyrrolidinyl, piperidinyl, pyrazolyl, triazolyl, or tetrazolyl.

In another embodiment, R³ is, independently at each occurrence, phenylsubstituted with 0-2 R^(3a) and 0-1 R^(3d), naphthyl substituted with0-2 R^(3a) and 0-1 R^(3d), or a 5- to 12-membered heterocyclesubstituted with 0-2 R^(3a) and 0-1 R^(3d), wherein said heterocycle isselected from: thiophene, furan, thiazole, tetrazole, pyridine,pyridone, pyrimidine, pyrrole, pyrazole, indole, 2-oxindole,isoindoline, indazole, 7-azaindole, benzofuran, benzothiophene,benzimidazole, benzisoxazole, benzoxazole, quinazoline, quinoline,isoquinoline, quinoxaline, phthalazine, dihydrophthalazine,dihydroisoquinoline, dihydroquinoline, dihydroquinolone, dihydroindole,dihydrobenzimidazole, dihydrobenzoxazine, dihydroquinazoline,dihydroquinoxaline, benzothiazine, benzoxazine, tetrahydrobenzazepine,dihydroazabenzocycloheptene, and tetrahydroquinoline.

In another embodiment, R³ is, independently at each occurrence, phenyl,3-biphenyl, 4-biphenyl, 3-aminophenyl, 4-aminophenyl,3-N,N-dimethylaminophenyl, 4-phenoxyphenyl, 4-benzyloxyphenyl,4-(t-butoxymethyl)-phenyl, 4-methylsulfonylphenyl, 3-cyanophenyl,4-cyanophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl,4-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 3-hydroxyphenyl,4-hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl,3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-carboxyphenyl,4-carboxyphenyl, 3-methoxycarbonylphenyl, 4-methoxycarbonylphenyl,3-carboxymethylphenyl, 4-carboxymethylphenyl,4-methoxycarbonylmethylphenyl, 3-ethoxycarbonylmethylphenyl,4-ethoxycarbonylmethylphenyl, 4-ethoxycarbonylethylphenyl,3-carbamoylphenyl, 4-carbamoylphenyl, 3-aminocarbonylmethylphenyl,4-aminocarbonylmethylphenyl, 4-methylaminocarbonylphenyl,4-dimethylaminocarbonylmethylphenyl, 4-amidinophenyl,3-methylcarbonylaminophenyl, 4-methylcarbonylaminophenyl,4-methoxycarbonylaminophenyl, 4-aminosulfonylphenyl,3-methylsulfonylaminophenyl, 4-methylsulfonylamino, 2,4-difluorophenyl,3-fluoro-4-cyanophenyl, 4-amino-3-carboxyphenyl,4-amino-3-methoxycarbonylphenyl, 2,4-dichlorophenyl,3-cyano-5-fluorophenyl, 3-fluoro-4-carbamoylphenyl,3-carboxy-4-cyanophenyl, 3-phenyl-4-carbamoylphenyl,4-(2-oxo-1-piperidino)-phenyl, thiazol-2-yl, thien-2-yl,4-methoxycarbonyl-thiazol-2-yl, 4-carbamoyl-thiazol-2-yl,1-benzyl-pyrazol-4-yl, 5-phenyl-oxazol-2-yl, 5-carbamoyl-thien-2-yl,5-carboxy-thien-2-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl,6-amino-pyrid-3-yl, benzimidazol-2-yl, 6-methoxy-pyrid-3-yl,1-methyl-benzimidazol-2-yl, benzoxazol-2-yl, benzothiazol-2-yl,3-amino-benzisoxazol-6-yl, 3-amino-benzisoxazol-5-yl, indazol-5-yl,indazol-6-yl, 3-amino-indazol-5-yl, 3-hydroxy-indazol-5-yl,3-amino-indazol-6-yl, 3-amino-1-methyl-indazol-6-yl,3-amino-4-fluoro-indazol-6-yl, 3-amino-5-fluoro-indazol-6-yl,3-amino-7-fluoro-indazol-6-yl,4-imino-3,4-dihydro-2H-phthalazin-1-on-7-yl, 3-(5-tetrazolyl)-phenyl,2,3-dihydro-isoindol-1-on-6-yl, quinolin-5-yl, quinolin-6-yl,quinolin-8-yl, isoquinolin-5-yl, 2H-isoquinolin-1-on-6-yl,2,4-diaminoquinazolin-7-yl, 4-NH₂-quinazolin-7-yl,

In another embodiment, R³ is, independently at each occurrence,

In another embodiment, R⁴ is, independently at each occurrence, H, Me,Et, Pr, F, Cl, Br, I, OCF₃, CF₃, CN, NO₂, —(CH₂)_(r)OH,—(CH₂)_(r)C(O)OR^(a), OR^(a), SR^(a), —C(O)R^(a), —C(O)OR^(a), —NR⁷R⁸,—(CH₂)_(r)NH₂, —NR⁸(CH₂)_(r)C(O)OR^(a), —(CH₂)_(r)C(O)NR⁸R⁹,—NR⁸C(O)R^(c), —NR⁸C(O)OR^(c), —NR⁸C(O)NR⁸R⁹, —S(O)_(p)NR⁸R⁹,—NR⁸S(O)_(p)R^(c), —S(O)_(p)R^(c) or phenyl substituted with 0-2 R^(4b).

In another embodiment, R⁴ is, independently at each occurrence, H, F,Cl, Br, OMe, OH, NH₂, NHMe, NHEt, NHPr, Me, Et, Pr,4-(methoxycarbonylamino)phenyl, CN, CF₃, —CH₂OH, —(CH₂)₂OH, —(CH₂)₃OH,—CH₂NH₂, —(CH₂)₂NH₂, —(CH₂)₃NH₂, CO₂H, —C(O)NH₂, —C(O)NHMe, —C(O)N(Me)₂,—CH₂CO₂H, —CH₂C(O)NH₂, —CH₂CH₂CO₂H, —NHC(O)Me, —NHCO₂Me, —NHC(O)NHMe,—NHC(O)N(Me)₂, —NHCH₂CO₂H, —NHSO₂Me, —SO₂NH₂, —SO₂NHMe, or —SO₂N(Me)₂.

In another embodiment, R⁴ is, independently at each occurrence, H, F,Cl, Br, OMe, OH, NH₂, Me, Et, Pr, CN, CF₃, —CH₂OH, —CH₂NH₂, —CO₂H,—C(O)NH₂, —C(O)NHMe, —C(O)N(Me)₂, —CH₂CO₂H, —CH₂C(O)NH₂, —CH₂CH₂CO₂H,—NHC(O)Me, —NHCO₂Me, —NHC(O)NHMe, —NHC(O)N(Me)₂, —NHCH₂CO₂H, or—NHSO₂Me.

In another embodiment, R¹¹ is C₁₋₄ haloalkyl, —CH₂C(O)NR⁸R⁹,—CH₂CH₂C(O)NR⁸R⁹, —CH₂C(O)R^(a), —CH₂CH₂C(O)R^(a), —CH₂C(O)OR^(a),—CH₂CH₂C(O)OR^(a), C₁₋₆ alkyl substituted with 0-2 R^(11c), C₂₋₆ alkenylsubstituted with 0-2 R^(11a), C₂₋₆ alkynyl substituted with 0-2 R^(11a),—(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(11b), or—(CH₂)_(r)-5- to 10-membered heterocycle comprising: carbon atoms and1-4 heteroatoms selected from N, O, and S(O)_(p), wherein saidheterocycle is substituted with 0-3 R^(11b).

In another embodiment, R¹¹ is —(CH₂)_(r)—C₃₋₁₀ carbocycle substitutedwith 0-3 R^(11b), or —(CH₂)_(r)-5- to 10-membered heterocyclecomprising: carbon atoms and 1-4 heteroatoms selected from N, O, andS(O)_(p), wherein said heterocycle is substituted with 0-3 R^(11b).

In another embodiment, R¹¹ is C₁₋₄ haloalkyl, —CH₂C(O)NR⁸R⁹,—CH₂CH₂C(O)NR⁸R⁹, —CH₂C(O)R^(a), —CH₂C(O)OR^(a), C₁₋₆ alkyl substitutedwith 0-2 R^(11c), —(CH₂)_(r)—C₃₋₇ cycloalkyl substituted with 0-2R^(11b), —(CH₂)_(r)-indanyl substituted with 0-2 R^(11b),—(CH₂)_(r)-indenyl substituted with 0-2 R^(11b), —(CH₂)_(r)-phenylsubstituted with 0-2 R^(11b), —(CH₂)_(r)-naphthyl substituted with 0-2R^(11b), or —(CH₂)_(r)-5- to 10-membered heterocycle comprising carbonatoms and 1-4 heteroatoms selected from N, O, and S(O)_(p), wherein saidheterocycle is substituted with 0-2 R^(11b).

In another embodiment, R¹¹ is —(CH₂)_(r)—C₃₋₇ cycloalkyl substitutedwith 0-2 R^(11b), —(CH₂)_(r)-indanyl substituted with 0-2 R^(11b),—(CH₂)_(r)-indenyl substituted with 0-2 R^(11b), —(CH₂)_(r)-phenylsubstituted with 0-2 R^(11b), —(CH₂)_(r)-naphthyl substituted with 0-2R^(11b), or —(CH₂)_(r)-5- to 10-membered heterocycle comprising carbonatoms and 1-4 heteroatoms selected from N, O, and S(O)_(p), wherein saidheterocycle is substituted with 0-2 R¹¹b.

In another embodiment, R¹¹ is C₁₋₄ haloalkyl, —CH₂C(O)NR⁸R⁹,—CH₂CH₂C(O)NR⁸R⁹, —CH₂C(O)R^(a), —CH₂CH₂C(O)R^(a), —CH₂C(O)OR^(a),—CH₂CH₂C(O)OR^(a), —CH₂OBn, —CH₂SBn, C₁₋₆ alkyl substituted with 0-2R^(11c), C₂₋₆ alkenyl substituted with 0-2 R^(11a), C₂₋₆ alkynylsubstituted with 0-2 R^(11a), —(CH₂)_(r)—C₃₋₇ cycloalkyl substitutedwith 0-2 R^(11b), —(CH₂)_(r)-phenyl substituted with 0-2 R^(11b),—(CH₂)_(r)-indanyl substituted with 0-2 R^(11b), —(CH₂)_(r)-indenylsubstituted with 0-2 R^(11b), —(CH₂)_(r)-naphthyl substituted with 0-2R^(11b), or —(CH₂)_(r)-5- to 10-membered heteroaryl substituted with 0-2R^(11b) and selected from thiazolyl, oxazolyl, pyrazolyl, triazolyl,tetrazolyl, thiadiazolyl, isoxazolyl, imidazolyl, pyridyl, pyrimidinyl,pyrazinyl, pyridazinyl, indolyl, indazolyl, isoindolyl, indolinyl,isoindolinyl, benzimidazolyl, benzothiazolyl, benzotriazolyl,quinolinyl, isoquinolinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and2,2-dioxo-2,3-dihydro-1H-2λ⁶-benzo[c]thiophenyl.

In another embodiment, R¹¹ is —CH₂OBn, —CH₂SBn, —(CH₂)_(r)—C₃₋₇cycloalkyl substituted with 0-2 R^(11b), —(CH₂)_(r)-phenyl substitutedwith 0-2 R^(11b), —(CH₂)_(r)-indanyl substituted with 0-2 R^(11b),—(CH₂)_(r)-indenyl substituted with 0-2 R^(11b), —(CH₂)_(r)-naphthylsubstituted with 0-2 R^(11b), or —(CH₂)_(r)-5- to 10-membered heteroarylsubstituted with 0-2 R^(11b) and selected from thiazolyl, oxazolyl,pyrazolyl, triazolyl, tetrazolyl, thiadiazolyl, isoxazolyl, imidazolyl,pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, indazolyl,isoindolyl, indolinyl, isoindolinyl, benzimidazolyl, benzothiazolyl,benzotriazolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and2,2-dioxo-2,3-dihydro-1H-2λ⁶-benzo[c]thiophenyl.

In another embodiment, R¹¹ is methyl, n-butyl, cyclohexylmethyl,carboxymethyl, benzyl, phenethyl, 2-fluorobenzyl, 3-fluorobenzyl,4-fluorobenzyl, 2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl,3-carboxybenzyl, 3-carbamoylbenzyl, 3-(N-methylcarbamoyl)-benzyl,3-(N,N-dimethylcarbamoyl)-benzyl, 3-(N-ethylcarbamoyl)-benzyl,3-methylbenzyl, 4-methylbenzyl, 3-methoxybenzyl,3-difluoromethoxybenzyl, 3-trifluoromethoxy-benzyl,3-methoxycarbonylbenzyl, 3-methylcarbonylamino-benzyl,3-benzylcarbonylamino-benzyl, 3-(benzoyl-methyl-amino)-benzyl,3-(2-phenylethyl)carbonylamino-benzyl, 2-phenylsulfonylamino-benzyl,3-phenylsulfonylamino-benzyl, 3-[N-methyl,N-phenylaminosulfonyl]-benzyl, 3-(benzenesulfonyl-methyl-amino)-benzyl,3-(2-methylphenyl)carbamoyl-benzyl, 3-(3-methylphenyl)carbamoyl-benzyl,3-(4-methylphenyl)carbamoyl-benzyl, 3-(4-fluorophenyl)carbamoyl-benzyl,3-(1-naphthyl)carbamoyl-benzyl, 3-benzylcarbamoyl-benzyl,3-(4-chlorophenyl)methylcarbamoyl-benzyl,3-(4-methoxyphenyl)methylcarbamoyl-benzyl,3-(2-phenylethyl)carbamoyl-benzyl,3-[2-(4-methoxyphenyl)ethyl]carbamoyl-benzyl,3-[2-(2-chlorophenyl)ethyl]carbamoyl-benzyl,3-[2-(3-chlorophenyl)ethyl]carbamoyl-benzyl,3-[2-(4-chlorophenyl)ethyl]carbamoyl-benzyl,3-[methyl-(pyridin-2-ylethyl)]carbamoyl-benzyl3-(3-phenylpropyl)carbamoyl-benzyl, 3-(ethyl-methyl-carbamoyl)-benzyl,3-(isopropyl-methyl-carbamoyl)-benzyl,3-(isobutyl-methyl-carbamoyl)-benzyl,3-(methyl-phenyl-carbamoyl)-benzyl,3-[(methyl-(3-methylphenyl)-carbamoyl]-benzyl,3-[methyl-(4-methylphenyl)-carbamoyl]-benzyl,3-(benzyl-methyl-carbamoyl)-benzyl,3-[(3-chlorobenzyl)-methyl-carbamoyl]-benzyl,3-[(4-chlorobenzyl)-methyl-carbamoyl]-benzyl,3-[methyl-phenethyl-carbamoyl)]-benzyl,3-(ethyl-phenyl-carbamoyl)-benzyl, 3-(piperidine-1-carbonyl)-benzyl,3-(3,4-dihydro-2H-quinoline-1-carbonyl)-benzyl,3-[(2-methoxyethyl)-methyl-carbamoyl]-benzyl,3-(4-methoxy-piperidine-1-carbonyl)-benzyl,3-(morpholine-4-sulfonyl)-benzyl, 3-[(N-(2-methoxyethyl),N-methylamino)sulfonyl]-benzyl, 3-(N,N-dimethylaminosulfonyl)-benzyl,3-(azetidine-1-carbonyl)-benzyl,3-(3-methoxy-azetidine-1-carbonyl)-benzyl,3-(3-hydroxy-pyrrolidine-1-carbonyl)-benzyl,3-[(4-tetrahydropyranyl)methylcarbonyl]-benzyl,3-[(2-hydroxyethyl)-methyl-carbamoyl]-benzyl,3-(3-hydroxy-azetidine-1-carbonyl)-benzyl,3-(4-hydroxypiperidine-1-carbonyl)-benzyl,3-[4-(N,N-dimethylamino)-piperidine-1-carbonyl]-benzyl,3-(4-methyl-piperazine-1-carbonyl)-benzyl,3-[3-(N,N-dimethylamino)-pyrrolidine-1-carbonyl]-benzyl,1-naphthylmethyl, 2-naphthylmethyl, thiazol-4-ylmethyl,pyrid-2-ylmethyl, pyrid-3-ylmethyl, pyrid-4-ylmethyl,1-benzyl-imidazol-4-ylmethyl, benzothiazol-2-ylmethyl,3-(1-morpholinocarbonyl)-benzyl,3-[(2,6-dimethylmorpholine-1-carbonyl)-benzyl,(benzyloxycarbonyl)methyl, (1-methylpyrazol-3-yl)methyl,(1-methylpyrazol-4-yl)methyl, (1-methylpyrazol-5-yl)methyl,(3-methylpyrazol-5-yl)methyl, (1-ethylpyrazol-4-yl)methyl,(1-n-propylpyrazol-4-yl)methyl, (1-isopropylpyrazol-4-yl)methyl,1-ethylpyrazol-3-ylmethyl, 3-pyrazolylmethyl,(4-chloro-3-methyl-5-pyrazolyl)methyl,(4-chloro-1,5-dimethyl-3-pyrazolyl)methyl,(4-chloro-1,3-dimethyl-5-pyrazolyl)methyl,[1-(4-methoxybenzyl)-pyrazol-3-yl]methyl,(1,5-dimethylpyrazol-3-yl)methyl, (1,3-dimethylpyrazol-5-yl)methyl,[1-(4-methoxybenzyl)-5-methyl-pyrazol-3-yl]methyl,(3-trifluoromethylpyrazol-5-yl)methyl,[1-(4-methoxybenzyl)-3-trifluoromethylpyrazol-5-yl]methyl,[(1-methyl-5-methoxycarbonyl)-pyrazol-3-yl]methyl,[(1-methyl-5-carboxy)-pyrazol-3-yl]methyl,[(1-methyl-5-carbamoyl)-pyrazol-3-yl]methyl,[(5-methoxycarbonyl)-pyrrol-2-yl]methyl, thiazol-2-ylmethyl,thiazol-4-methyl, (2-methoxypyridin-3-yl)methyl,(6-methoxypyridin-3-yl)methyl, (4-(methoxycarbonyl)-oxazol-2-yl)methyl,morpholin-4-ylcarbonylmethyl,N-((5-methylpyrazin-2-yl)methyl)-aminocarbonylmethyl,2-hydroxy-indan-5-ylmethyl, 4-methylpiperazin-1-ylcarbonylmethyl,4-methylcarbonylpiperazin-1-ylcarbonylmethyl,pyrrolidin-1-ylcarbonylmethyl, 2-methoxypyrrolidin-1-ylcarbonylmethyl,aziridin-1-ylcarbonylmethyl, 2-hydroxyethylaminocarbonylmethyl,2-methoxyethylaminocarbonylmethyl, 2-ethoxyethylaminocarbonylmethyl,bis(2-methoxyethyl)aminocarbonylmethyl,4-dimethylaminopyrrolidin-1-ylcarbonylmethyl,4-chlorophenylaminocarbonylmethyl, 3-chlorophenylcarbonylmethyl,N-methyl-N-benzylaminocarbonylmethyl, cyclopropylaminocarbonylmethyl,cyclopropylmethylaminocarbonylmethyl, cyclopentylaminocarbonylmethyl,(trans-2-phenylcyclopropyl)aminocarbonylmethyl,N,N-dimethylaminoethylaminocarbonylmethyl,N-((pyridin-2-yl)methyl)-aminocarbonylmethyl,N-((pyridin-3-yl)methyl)-aminocarbonylmethyl,N-((pyridin-4-yl)methyl)-aminocarbonylmethyl,N-((pyridin-2-yl)ethyl)-aminocarbonylmethyl,1-(1,1-dioxo-1λ⁶-thiomorpholin-4-yl)carbonylmethyl,N-(tert-butoxycarbonyl)-1H-indol-3-ylmethyl, 1H-indol-3-ylmethyl,2,2-dioxo-2,3-dihydro-1H-2λ⁶-benzo[c]thiophen-5-ylmethyl,4,4,4-trifluorobutyl, cyclopropylmethyl, (4-hydroxy)cyclohexylmethyl,4-oxo-cyclohexylmethyl,

In another embodiment, R¹¹ is cyclohexylmethyl, benzyl, phenethyl,2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl, 2-chlorobenzyl,3-chlorobenzyl, 4-chlorobenzyl, 3-carboxybenzyl, 3-carbamoylbenzyl,3-(N-methylcarbamoyl)-benzyl, 3-(N,N-dimethylcarbamoyl)-benzyl,3-(N-ethylcarbamoyl)-benzyl, 3-methylbenzyl, 4-methylbenzyl,3-methoxybenzyl, 3-difluoromethoxybenzyl, 3-trifluoromethoxy-benzyl,3-methoxycarbonylbenzyl, 3-methylcarbonylamino-benzyl,3-benzylcarbonylamino-benzyl, 3-(benzoyl-methyl-amino)-benzyl,3-(2-phenylethyl)carbonylamino-benzyl, 2-phenylsulfonylamino-benzyl,3-phenylsulfonylamino-benzyl, 3-[N-methyl,N-phenylaminosulfonyl]-benzyl, 3-(benzenesulfonyl-methyl-amino)-benzyl,3-(2-methylphenyl)carbamoyl-benzyl, 3-(3-methylphenyl)carbamoyl-benzyl,3-(4-methylphenyl)carbamoyl-benzyl, 3-(4-fluorophenyl)carbamoyl-benzyl,3-(1-naphthyl)carbamoyl-benzyl, 3-benzylcarbamoyl-benzyl,3-(4-chlorophenyl)methylcarbamoyl-benzyl,3-(4-methoxyphenyl)methylcarbamoyl-benzyl,3-(2-phenylethyl)carbamoyl-benzyl,3-[2-(4-methoxyphenyl)ethyl]carbamoyl-benzyl,3-[2-(2-chlorophenyl)ethyl]carbamoyl-benzyl,3-[2-(3-chlorophenyl)ethyl]carbamoyl-benzyl,3-[2-(4-chlorophenyl)ethyl]carbamoyl-benzyl,3-[methyl-(pyridin-2-ylethyl)]carbamoyl-benzyl3-(3-phenylpropyl)carbamoyl-benzyl, 3-(ethyl-methyl-carbamoyl)-benzyl,3-(isopropyl-methyl-carbamoyl)-benzyl,3-(isobutyl-methyl-carbamoyl)-benzyl,3-(methyl-phenyl-carbamoyl)-benzyl,3-[(methyl-(3-methylphenyl)-carbamoyl]-benzyl,3-[methyl-(4-methylphenyl)-carbamoyl]-benzyl,3-(benzyl-methyl-carbamoyl)-benzyl,3-[(3-chlorobenzyl)-methyl-carbamoyl]-benzyl,3-[(4-chlorobenzyl)-methyl-carbamoyl]-benzyl,3-[methyl-phenethyl-carbamoyl)]-benzyl,3-(ethyl-phenyl-carbamoyl)-benzyl, 3-(piperidine-1-carbonyl)-benzyl,3-(3,4-dihydro-2H-quinoline-1-carbonyl)-benzyl,3-[(2-methoxyethyl)-methyl-carbamoyl]-benzyl,3-(4-methoxy-piperidine-1-carbonyl)-benzyl,3-(morpholine-4-sulfonyl)-benzyl, 3-[(N-(2-methoxyethyl),N-methylamino)sulfonyl]-benzyl, 3-(N,N-dimethylaminosulfonyl)-benzyl,3-(azetidine-1-carbonyl)-benzyl,3-(3-methoxy-azetidine-1-carbonyl)-benzyl,3-(3-hydroxy-pyrrolidine-1-carbonyl)-benzyl,3-[(4-tetrahydropyranyl)methylcarbonyl]-benzyl,3-[(2-hydroxyethyl)-methyl-carbamoyl]-benzyl,3-(3-hydroxy-azetidine-1-carbonyl)-benzyl,3-(4-hydroxypiperidine-1-carbonyl)-benzyl,3-[4-(N,N-dimethylamino)-piperidine-1-carbonyl]-benzyl,3-(4-methyl-piperazine-1-carbonyl)-benzyl,3-[3-(N,N-dimethylamino)-pyrrolidine-1-carbonyl]-benzyl,1-naphthylmethyl, 2-naphthylmethyl, thiazol-4-ylmethyl,pyrid-2-ylmethyl, pyrid-3-ylmethyl, pyrid-4-ylmethyl,1-benzyl-imidazol-4-ylmethyl, benzothiazol-2-ylmethyl,3-(1-morpholinocarbonyl)-benzyl,3-[(2,6-dimethylmorpholine-1-carbonyl)-benzyl,(benzyloxycarbonyl)methyl, (1-methylpyrazol-3-yl)methyl,(1-methylpyrazol-4-yl)methyl, (1-methylpyrazol-5-yl)methyl,(3-methylpyrazol-5-yl)methyl, (1-ethylpyrazol-4-yl)methyl,(1-n-propylpyrazol-4-yl)methyl, (1-isopropylpyrazol-4-yl)methyl,1-ethylpyrazol-3-ylmethyl, 3-pyrazolylmethyl,(4-chloro-3-methyl-5-pyrazolyl)methyl,(4-chloro-1,5-dimethyl-3-pyrazolyl)methyl,(4-chloro-1,3-dimethyl-5-pyrazolyl)methyl,[1-(4-methoxybenzyl)-pyrazol-3-yl]methyl,(1,5-dimethylpyrazol-3-yl)methyl, (1,3-dimethylpyrazol-5-yl)methyl,[1-(4-methoxybenzyl)-5-methyl-pyrazol-3-yl]methyl,(3-trifluoromethylpyrazol-5-yl)methyl,[1-(4-methoxybenzyl)-3-trifluoromethylpyrazol-5-yl]methyl,[(1-methyl-5-methoxycarbonyl)-pyrazol-3-yl]methyl,[(1-methyl-5-carboxy)-pyrazol-3-yl]methyl,[(1-methyl-5-carbamoyl)-pyrazol-3-yl]methyl,[(5-methoxycarbonyl)-pyrrol-2-yl]methyl, thiazol-2-ylmethyl,thiazol-4-methyl, (2-methoxypyridin-3-yl)methyl,(6-methoxypyridin-3-yl)methyl, (4-(methoxycarbonyl)-oxazol-2-yl)methyl,morpholin-4-ylcarbonylmethyl,N-((5-methylpyrazin-2-yl)methyl)-aminocarbonylmethyl,2-hydroxy-indan-5-ylmethyl, 4-methylpiperazin-1-ylcarbonylmethyl,4-methylcarbonylpiperazin-1-ylcarbonylmethyl,pyrrolidin-1-ylcarbonylmethyl, 2-methoxypyrrolidin-1-ylcarbonylmethyl,aziridin-1-ylcarbonylmethyl, 2-hydroxyethylaminocarbonylmethyl,2-methoxyethylaminocarbonylmethyl, 2-ethoxyethylaminocarbonylmethyl,bis(2-methoxyethyl)aminocarbonylmethyl,4-dimethylaminopyrrolidin-1-ylcarbonylmethyl,4-chlorophenylaminocarbonylmethyl, 3-chlorophenylcarbonylmethyl,N-methyl-N-benzylaminocarbonylmethyl, cyclopropylaminocarbonylmethyl,cyclopropylmethylaminocarbonylmethyl, cyclopentylaminocarbonylmethyl,(trans-2-phenylcyclopropyl)aminocarbonylmethyl,N,N-dimethylaminoethylaminocarbonylmethyl,N-((pyridin-2-yl)methyl)-aminocarbonylmethyl,N-((pyridin-3-yl)methyl)-aminocarbonylmethyl,N-((pyridin-4-yl)methyl)-aminocarbonylmethyl,N-((pyridin-2-yl)ethyl)-aminocarbonylmethyl,1-(1,1-dioxo-1λ⁶-thiomorpholin-4-yl)carbonylmethyl,N-(tert-butoxycarbonyl)-1H-indol-3-ylmethyl, 1H-indol-3-ylmethyl,2,2-dioxo-2,3-dihydro-1H-2λ⁶-benzo[c]thiophen-5-ylmethyl,4,4,4-trifluorobutyl, cyclopropylmethyl, (4-hydroxy)cyclohexylmethyl,4-oxo-cyclohexylmethyl,

In another embodiment the present invention provides a pharmaceuticalcomposition comprising a pharmaceutically acceptable carrier and atleast one of the compounds of the present invention or stereoisomers,tautomers, pharmaceutically acceptable salts, solvates, or prodrugsthereof.

In another embodiment, the present invention provides a novelpharmaceutical composition, comprising: a pharmaceutically acceptablecarrier and a therapeutically effective amount of at least one of thecompounds of the present invention or stereoisomers, tautomers,pharmaceutically acceptable salts, solvates, or prodrugs thereof.

In another embodiment, the present invention provides a novel processfor making a compound of the present invention or stereoisomers,tautomers, pharmaceutically acceptable salts, solvates, or prodrugsthereof.

In another embodiment, the present invention provides a novelintermediate for making a compound of the present invention orstereoisomers, tautomers, pharmaceutically acceptable salts, solvates,or prodrugs thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition further comprising additional therapeutic agent(s) selectedfrom potassium channel openers, potassium channel blockers, calciumchannel blockers, sodium hydrogen exchanger inhibitors, antiarrhythmicagents, antiatherosclerotic agents, anticoagulants, antithromboticagents, prothrombolytic agents, fibrinogen antagonists, diuretics,antihypertensive agents, ATPase inhibitors, mineralocorticoid receptorantagonists, phosphodiesterase inhibitors, antidiabetic agents,anti-inflammatory agents, antioxidants, angiogenesis modulators,antiosteoporosis agents, hormone replacement therapies, hormone receptormodulators, oral contraceptives, antiobesity agents, antidepressants,antianxiety agents, antipsychotic agents, antiproliferative agents,antitumor agents, antiulcer and gastroesophageal reflux disease agents,growth hormone agents and/or growth hormone secretagogues, thyroidmimetics, anti-infective agents, antiviral agents, antibacterial agents,antifungal agents, cholesterol/lipid lowering agents and lipid profiletherapies, and agents that mimic ischemic preconditioning and/ormyocardial stunning, or a combination thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition further comprising additional therapeutic agent(s) selectedfrom an anti-arrhythmic agent, an anti-hypertensive agent, ananti-coagulant agent, an anti-platelet agent, a thrombin inhibitingagent, a thrombolytic agent, a fibrinolytic agent, a calcium channelblocker, a potassium channel blocker, a cholesterol/lipid loweringagent, or a combination thereof.

In another embodiment, the present invention provides a pharmaceuticalcomposition further comprising additional therapeutic agent(s) selectedfrom warfarin, unfractionated heparin, low molecular weight heparin,synthetic pentasaccharide, hirudin, argatroban, aspirin, ibuprofen,naproxen, sulindac, indomethacin, mefenamate, dipyridamol, droxicam,diclofenac, sulfinpyrazone, piroxicam, ticlopidine, clopidogrel,tirofiban, eptifibatide, abciximab, melagatran, ximelagatran,disulfatohirudin, tissue plasminogen activator, modified tissueplasminogen activator, anistreplase, urokinase, and streptokinase, or acombination thereof.

In a preferred embodiment, the present invention provides apharmaceutical composition wherein the additional therapeutic agent isan antihypertensive agent selected from ACE inhibitors, AT-1 receptorantagonists, beta-adrenergic receptor antagonists, ETA receptorantagonists, dual ETA/AT-1 receptor antagonists, and vasopepsidaseinhibitors, an antiarrythmic agent selected from IKur inhibitors, ananticoagulant selected from thrombin inhibitors, antithrombin-IIIactivators, heparin co-factor II activators, other factor XIainhibitors, other kallikrein inhibitors, plasminogen activator inhibitor(PAI-1) antagonists, thrombin activatable fibrinolysis inhibitor (TAFI)inhibitors, factor VIIa inhibitors, factor IXa inhibitors, and factor Xainhibitors, or an antiplatelet agent selected from GPIIb/IIIa blockers,protease activated receptor (PAR-1) antagonists, phosphodiesterase-IIIinhibitors, P2Y₁ receptor antagonists, P2Y₁₂ antagonists, thromboxanereceptor antagonists, cyclooxygense-1 inhibitors, and aspirin, or acombination thereof.

In a preferred embodiment, the present invention provides pharmaceuticalcomposition, wherein the additional therapeutic agent(s) are ananti-platelet agent or a combination thereof.

In a preferred embodiment, the present invention provides apharmaceutical composition, wherein the additional therapeutic agent isthe anti-platelet agent clopidogrel.

In another embodiment the present invention provides a method formodulation of the coagulation cascade and/or contact activation systemcomprising administering to a patient in need of such treatment atherapeutically effective amount of at least one of the compounds of thepresent invention or a stereoisomer, tautomer, pharmaceuticallyacceptable salt, solvate or prodrug thereof.

In another embodiment, the present invention provides a novel method fortreating thrombotic or thromboembolic disorders comprising:administering to a patient in need of such treatment a therapeuticallyeffective amount of at least one of the compounds of the presentinvention or a stereoisomer, tautomer, pharmaceutically acceptable salt,solvate or prodrug thereof.

In another embodiment, the present invention provides a novel method,wherein the thromboembolic disorder is selected from the groupconsisting of arterial cardiovascular thromboembolic disorders, venouscardiovascular thromboembolic disorders, arterial cerebrovascularthromboembolic disorders, and venous cerebrovascular thromboembolicdisorders.

In another embodiment, the present invention provides a novel method,wherein the thromboembolic disorder is selected from unstable angina, anacute coronary syndrome, atrial fibrillation, first myocardialinfarction, recurrent myocardial infarction, ischemic sudden death,transient ischemic attack, stroke, atherosclerosis, peripheral occlusivearterial disease, venous thrombosis, deep vein thrombosis,thrombophlebitis, arterial embolism, coronary arterial thrombosis,cerebral arterial thrombosis, cerebral embolism, kidney embolism,pulmonary embolism, and thrombosis resulting from medical implants,devices, or procedures in which blood is exposed to an artificialsurface that promotes thrombosis.

In another embodiment, the present invention provides a method fortreating inflammatory disorders comprising: administering to a patientin need of such treatment a therapeutically effective amount of at leastone of the compounds of the present invention or stereoisomers,tautomers, pharmaceutically acceptable salts, solvates, or prodrugsthereof.

In another embodiment, the present invention provides a method, whereinthe inflammatory disorder is selected from the group consisting ofsepsis, acute respiratory distress syndrome, and systemic inflammatoryresponse syndrome.

In another embodiment, the present invention provides a novel method oftreating a patient in need of thromboembolic disorder treatment,comprising: administering a compound of the present invention orstereoisomers, tautomers, pharmaceutically acceptable salts, solvates,or prodrugs form thereof in an amount effective to treat a thrombotic orthromboembolic disorder.

In another embodiment, the present invention provides a novel article ofmanufacture, comprising: (a) a first container; (b) a pharmaceuticalcomposition located within the first container, wherein the composition,comprises: a first therapeutic agent, comprising: a compound of thepresent invention; and (c) a package insert stating that thepharmaceutical composition can be used for the treatment of athromboembolic and/or inflammatory disorder.

In another preferred embodiment, the present invention provides a novelarticle of manufacture, further comprising: (d) a second container;wherein components (a) and (b) are located within the second containerand component (c) is located within or outside of the second container.

In another embodiment, the present invention provides a novel article ofmanufacture, comprising: (a) a first container; (b) a pharmaceuticalcomposition located within the first container, wherein the composition,comprises: a first therapeutic agent, comprising: a compound of thepresent invention; and (c) a package insert stating that thepharmaceutical composition can be used in combination with a secondtherapeutic agent to treat a thromboembolic and/or inflammatorydisorder.

In another preferred embodiment, the present invention provides a novelarticle of manufacture, further comprising: (d) a second container;wherein components (a) and (b) are located within the second containerand component (c) is located within or outside of the second container.

In another embodiment, the present invention provides a novel method,comprising: administering a compound of the present invention orstereoisomers, tautomers, pharmaceutically acceptable salts, solvates,or prodrugs thereof in an amount effective to treat a thromboembolicand/or inflammatory disorder.

In another embodiment, the present invention provides a compound of thepresent invention or stereoisomers, tautomers, pharmaceuticallyacceptable salts, solvates, or prodrugs thereof, for use in therapy.

In another embodiment, the present invention provides a compound of thepresent invention or stereoisomers, tautomers, pharmaceuticallyacceptable salts, solvates, or prodrugs thereof, for use in therapy fortreating a thromboembolic and/or inflammatory disorder.

In another embodiment, the present invention also provides the use of acompound of the present invention or stereoisomers, tautomers,pharmaceutically acceptable salts, solvates, or prodrugs thereof, forthe manufacture of a medicament for the treatment of a thromboembolicand/or inflammatory disorder.

The present invention may be embodied in other specific forms withoutdeparting from the spirit or essential attributes thereof. Thisinvention encompasses all combinations of preferred aspects of theinvention noted herein. It is understood that any and all embodiments ofthe present invention may be taken in conjunction with any otherembodiment or embodiments to describe additional more preferredembodiments. It is also to be understood that each individual element ofthe preferred embodiments is its own independent preferred embodiment.Furthermore, any element of an embodiment is meant to be combined withany and all other elements from any embodiment to describe an additionalembodiment.

DEFINITIONS

Compounds of this invention may have one or more asymmetric centers.Unless otherwise indicated, all chiral (enantiomeric and diastereomeric)and racemic forms of compounds of the present invention are included inthe present invention. Many geometric isomers of olefins, C═N doublebonds, and the like can also be present in the compounds, and all suchstable isomers are contemplated in the present invention. Cis and transgeometric isomers of the compounds of the present invention aredescribed and may be isolated as a mixture of isomers or as separatedisomeric forms. The present compounds can be isolated in opticallyactive or racemic forms. It is well known in the art how to prepareoptically active forms, such as by resolution of racemic forms or bysynthesis from optically active starting materials. All chiral,(enantiomeric and diastereomeric) and racemic forms and all geometricisomeric forms of a structure are intended, unless the specificstereochemistry or isomer form is specifically indicated. When nospecific mention is made of the configuration (cis, trans or R or S) ofa compound (or of an asymmetric carbon), then any one of the isomers ora mixture of more than one isomer is intended. The processes forpreparation can use racemates, enantiomers, or diastereomers as startingmaterials. All processes used to prepare compounds of the presentinvention and intermediates made therein are considered to be part ofthe present invention. When enantiomeric or diastereomeric products areprepared, they can be separated by conventional methods, for example, bychromatography or fractional crystallization. Compounds of the presentinvention, and salts thereof, may exist in multiple tautomeric forms, inwhich hydrogen atoms are transposed to other parts of the molecules andthe chemical bonds between the atoms of the molecules are consequentlyrearranged. It should be understood that all tautomeric forms, insofaras they may exist, are included within the invention. The inventivecompounds may be in the free or hydrate form.

Preferably, the molecular weight of compounds of the present inventionis less than about 500, 550, 600, 650, 700, 750, or 800 grams per mole.Preferably, the molecular weight is less than about 800 grams per mole.More preferably, the molecular weight is less than about 750 grams permole. Even more preferably, the molecular weight is less than about 700grams per mole.

As used herein, the term “alkyl” or “alkylene” is intended to includeboth branched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms. For example, “C₁₋₁₀ alkyl”(or alkylene), is intended to include C₁, C₂, C₃, C₄, C₅, C₆, C₇, C₈,C₉, and C₁₀ alkyl groups. Additionally, for example, “C₁-C₆ alkyl”denotes alkyl having 1 to 6 carbon atoms. Alkyl groups can beunsubstituted or substituted so that one or more of its hydrogens arereplaced by another chemical group. Example alkyl groups include, butare not limited to, methyl (Me), ethyl (Et), propyl (e.g., n-propyl andisopropyl), butyl (e.g., n-butyl, isobutyl, t-butyl), pentyl (e.g.n-pentyl, isopentyl, neopentyl), and the like.

Alkenyl” or “alkenylene” is intended to include hydrocarbon chains ofeither straight or branched configuration and having one or more doublecarbon-carbon bonds that may occur in any stable point along the chain.For example, “C₂₋₆ alkenyl” (or alkenylene), is intended to include C₂,C₃, C₄, C₅, and C₆ alkenyl groups. Examples of alkenyl include, but arenot limited to, ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl,2-pentenyl, 3, pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl,5-hexenyl, 2-methyl-2-propenyl, 4-methyl-3-pentenyl, and the like.

“Alkynyl” or “alkynylene” is intended to include hydrocarbon chains ofeither straight or branched configuration and having one or more triplecarbon-carbon bonds that may occur in any stable point along the chain.For example, “C₂₋₆ alkynyl” (or alkynylene), is intended to include C₂,C₃, C₄, C₅, and C₆ alkynyl groups; such as ethynyl, propynyl, butynyl,pentynyl, hexynyl and the like.

The term “alkoxy” or “alkyloxy” refers to an —O-alkyl group “C₁₋₆alkoxy” (or alkyloxy), is intended to include C₁, C₂, C₃, C₄, C₅, and C₆alkoxy groups. Example alkoxy groups include, but are not limited to,methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), and t-butoxy,and the like. Similarly, “alkylthio” or “thioalkoxy” represents an alkylgroup as defined above with the indicated number of carbon atomsattached through a sulphur bridge; for example methyl-S—, ethyl-S—, andthe like.

“Halo” or “halogen” includes fluoro, chloro, bromo, and iodo.“Haloalkyl” is intended to include both branched and straight-chainsaturated aliphatic hydrocarbon groups having the specified number ofcarbon atoms, substituted with 1 or more halogen. Examples of haloalkylinclude, but are not limited to, fluoromethyl, difluoromethyl,trifluoromethyl, trichloromethyl, pentafluoroethyl, pentachloroethyl,2,2,2-trifluoroethyl, heptafluoropropyl, and heptachloropropyl. Examplesof haloalkyl also include “fluoroalkyl” which is intended to includeboth branched and straight-chain saturated aliphatic hydrocarbon groupshaving the specified number of carbon atoms, substituted with 1 or morefluorine atoms.

“Haloalkoxy” or “haloalkyloxy” represents a haloalkyl group as definedabove with the indicated number of carbon atoms attached through anoxygen bridge. For example, “C₁₋₆ haloalkoxy”, is intended to includeC₁, C₂, C₃, C₄, C₅, and C₆ haloalkoxy groups. Examples of haloalkoxyinclude, but are not limited to, trifluoromethoxy,2,2,2-trifluoroethoxy, pentafluorothoxy, and the like. Similarly,“haloalkylthio” or “thiohaloalkoxy” represents a haloalkyl group asdefined above with the indicated number of carbon atoms attached througha sulphur bridge; for example trifluoromethyl-S—, pentafluoroethyl-S—,and the like.

The term “cycloalkyl” refers to cyclized alkyl groups, including mono-,bi- or poly-cyclic ring systems. C₃₋₇ cycloalkyl is intended to includeC₃, C₄, C₅, C₆, and C₇ cycloalkyl groups. Example cycloalkyl groupsinclude, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, norbornyl, and the like.

As used herein, “carbocycle” or “carbocyclic residue” is intended tomean any stable 3, 4, 5, 6, or 7-membered monocyclic or bicyclic or 7,8, 9, 10, 11, 12, or 13-membered bicyclic or tricyclic ring, any ofwhich may be saturated, partially unsaturated, unsaturated or aromatic.Examples of such carbocycles include, but are not limited to,cyclopropyl, cyclobutyl, cyclobutenyl, cyclopentyl, cyclopentenyl,cyclohexyl, cycloheptenyl, cycloheptyl, cycloheptenyl, adamantyl,cyclooctyl, cyclooctenyl, cyclooctadienyl, [3.3.0]bicyclooctane,[4.3.0]bicyclononane, [4.4.0]bicyclodecane, [2.2.2]bicyclooctane,fluorenyl, phenyl, naphthyl, indanyl, adamantyl, anthracenyl, andtetrahydronaphthyl (tetralin). As shown above, bridged rings are alsoincluded in the definition of carbocycle (e.g., [2.2.2]bicyclooctane).Preferred carbocycles, unless otherwise specified, are cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, phenyl, and indanyl. When the term“carbocycle” is used, it is intended to include “aryl”. A bridged ringoccurs when one or more carbon atoms link two non-adjacent carbon atoms.Preferred bridges are one or two carbon atoms. It is noted that a bridgealways converts a monocyclic ring into a tricyclic ring. When a ring isbridged, the substituents recited for the ring may also be present onthe bridge.

“Aryl” groups refer to monocyclic or polycyclic aromatic hydrocarbons,including, for example, phenyl, naphthyl, phenanthranyl, and the like.Aryl moieties are well known and described, for example, in Hawley'sCondensed Chemical Dictionary (13 ed.), R. J. Lewis, ed., J. Wiley &Sons, Inc., New York (1997). Unless otherwise specified, “aryl”, “C₆₋₁₀aryl” or “aromatic residue” may be unsubstituted or substituted with 0to 3 groups selected from H, OH, OCH₃, Cl, F, Br, I, CN, NO₂, NH₂,N(CH₃)H, N(CH₃)₂, CF₃, OCF₃, C(═O)CH₃, SCH₃, S(═O)CH₃, S(═O)₂CH₃, CH₃,CH₂CH₃, CO₂H, and CO₂CH₃.

As used herein, the term “heterocycle” or “heterocyclic group” isintended to mean a stable 5, 6, or 7-membered monocyclic or bicyclic or7, 8, 9, 10, 11, 12, 13, or 14-membered bicyclic heterocyclic ring whichis saturated, partially unsaturated or fully unsaturated, and whichconsists of carbon atoms and 1, 2, 3 or 4 heteroatoms independentlyselected from N, O and S; and including any bicyclic group in which anyof the above-defined heterocyclic rings is fused to a benzene ring. Thenitrogen and sulfur heteroatoms may optionally be oxidized (i.e., N→Oand S(O)p). The nitrogen atom may be substituted or unsubstituted (i.e.,N or NR wherein R is H or another substituent, if defined). Theheterocyclic ring may be attached to its pendant group at any heteroatomor carbon atom that results in a stable structure. The heterocyclicrings described herein may be substituted on carbon or on a nitrogenatom if the resulting compound is stable. A nitrogen in the heterocyclemay optionally be quaternized. It is preferred that when the totalnumber of S and O atoms in the heterocycle exceeds 1, then theseheteroatoms are not adjacent to one another. It is preferred that thetotal number of S and O atoms in the heterocycle is not more than 1.When the term “heterocycle” is used, it is intended to includeheteroaryl.

Examples of heterocycles include, but are not limited to, acridinyl,azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzoxazolyl,benzoxazolinyl, benzthiazolyl, benztriazolyl, benztetrazolyl,benzisoxazolyl, benzisothiazolyl, benzimidazolinyl, carbazolyl,4aH-carbazolyl, carbolinyl, chromanyl, chromenyl, cinnolinyl,decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]tetrahydrofuran, furanyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolenyl, indolinyl,indolizinyl, indolyl, 3H-indolyl, isatinoyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl,isothiazolyl, isothiazolopyridinyl, isoxazolyl, isoxazolopyridinyl,methylenedioxyphenyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxindolyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, piperidonyl, 4-piperidonyl, piperonyl,pteridinyl, purinyl, pyranyl, pyrazinyl, pyrazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,pyridinyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2-pyrrolidonyl,2H-pyrrolyl, pyrrolyl, quinazolinyl, quinolinyl, 4H-quinolizinyl,quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, tetrazolyl, 6H-1,2,5-thiadiazinyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thianthrenyl, thiazolyl, thienyl, thienothiazolyl,thienooxazolyl, thienoimidazolyl, thiophenyl, triazinyl,1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl, 1,3,4-triazolyl, andxanthenyl. Also included are fused ring and spiro compounds containing,for example, the above heterocycles.

Preferred 5- to 10-membered heterocycles include, but are not limitedto, pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl,piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl,tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl,oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl,triazinyl, triazolyl, benzimidazolyl, 1H-indazolyl, benzofuranyl,benzothiofuranyl, benztetrazolyl, benzotriazolyl, benzisoxazolyl,benzoxazolyl, oxindolyl, benzoxazolinyl, benzthiazolyl,benzisothiazolyl, isatinoyl, isoquinolinyl, octahydroisoquinolinyl,tetrahydroisoquinolinyl, tetrahydroquinolinyl, isoxazolopyridinyl,quinazolinyl, quinolinyl, isothiazolopyridinyl, thiazolopyridinyl,oxazolopyridinyl, imidazolopyridinyl, and pyrazolopyridinyl.

Preferred 5 to 6 membered heterocycles include, but are not limited to,pyridinyl, furanyl, thienyl, pyrrolyl, pyrazolyl, pyrazinyl,piperazinyl, piperidinyl, imidazolyl, imidazolidinyl, indolyl,tetrazolyl, isoxazolyl, morpholinyl, oxazolyl, oxadiazolyl,oxazolidinyl, tetrahydrofuranyl, thiadiazinyl, thiadiazolyl, thiazolyl,triazinyl, and triazolyl. Also included are fused ring and spirocompounds containing, for example, the above heterocycles.

As used herein, the term “aromatic heterocyclic group” or “heteroaryl”is intended to mean a stable monocyclic and polycyclic aromatichydrocarbons that include at least one heteroatom ring member such assulfur, oxygen, or nitrogen. Heteroaryl groups include, withoutlimitation, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,furyl, quinolyl, isoquinolyl, thienyl, imidazolyl, thiazolyl, indolyl,pyrroyl, oxazolyl, benzofuryl, benzothienyl, benzthiazolyl, isoxazolyl,pyrazolyl, triazolyl, tetrazolyl, indazolyl, 1,2,4-thiadiazolyl,isothiazolyl, purinyl, carbazolyl, benzimidazolyl, indolinyl,benzodioxolanyl, benzodioxane, and the like. Heteroaryl groups can besubstituted or unsubstituted. The nitrogen atom may be substituted orunsubstituted (i.e., N or NR wherein R is H or another substituent, ifdefined). The nitrogen and sulfur heteroatoms may optionally be oxidized(i.e., N→O and S(O)_(p)). It is to be noted that total number of S and Oatoms in the aromatic heterocycle is not more than 1. Bridged rings arealso included in the definition of heterocycle. A bridged ring occurswhen one or more atoms (i.e., C, O, N, or S) link two non-adjacentcarbon or nitrogen atoms. Preferred bridges include, but are not limitedto, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogenatoms, and a carbon-nitrogen group. It is noted that a bridge alwaysconverts a monocyclic ring into a tricyclic ring. When a ring isbridged, the substituents recited for the ring may also be present onthe bridge.

The term “counterion” is used to represent a small, negatively chargedspecies such as chloride, bromide, hydroxide, acetate, sulfate, and thelike.

As referred to herein, the term “substituted” means that one or morehydrogen atoms is replaced with a non-hydrogen group, provided thatnormal valencies are maintained and that the substitution results in astable compound. When a substituent is keto (i.e., ═O), then 2 hydrogenson the atom are replaced. Keto substituents are not present on aromaticmoieties. When a ring system (e.g., carbocyclic or heterocyclic) is saidto be substituted with a carbonyl group or a double bond, it is intendedthat the carbonyl group or double bond be part (i.e., within) of thering. Ring double bonds, as used herein, are double bonds that areformed between two adjacent ring atoms (e.g., C═C, C═N, or N═N).

In cases wherein there are nitrogen atoms (e.g., amines) on compounds ofthe present invention, these may be converted to N-oxides by treatmentwith an oxidizing agent (e.g., mCPBA and/or hydrogen peroxides) toafford other compounds of this invention. Thus, shown and claimednitrogen atoms are considered to cover both the shown nitrogen and itsN-oxide (N→O) derivative. In cases wherein there are quaternary carbonatoms on compounds of the present invention, these can be replaced bysilicon atoms, provided they do not form Si—N or Si—O bond.

When any variable occurs more than one time in any constituent orformula for a compound, its definition at each occurrence is independentof its definition at every other occurrence. Thus, for example, if agroup is shown to be substituted with 0-3 R^(3a), then said group mayoptionally be substituted with up to three R^(3a) groups and R^(3a) ateach occurrence is selected independently from the definition of R^(3a).Also, combinations of substituents and/or variables are permissible onlyif such combinations result in stable compounds.

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any atom on thering. When a substituent is listed without indicating the atom via whichsuch substituent is bonded to the rest of the compound of a givenformula, then such substituent may be bonded via any atom in suchsubstituent. Combinations of substituents and/or variables arepermissible only if such combinations result in stable compounds.

The phrase “pharmaceutically acceptable” is employed herein to refer tothose compounds, materials, compositions, and/or dosage forms which are,within the scope of sound medical judgment, suitable for use in contactwith the tissues of human beings and animals without excessive toxicity,irritation, allergic response, or other problem or complication,commensurate with a reasonable benefit/risk ratio.

As used herein, “pharmaceutically acceptable salts” refer to derivativesof the disclosed compounds wherein the parent compound is modified bymaking acid or base salts thereof. Examples of pharmaceuticallyacceptable salts include, but are not limited to, mineral or organicacid salts of basic groups such as amines; and alkali or organic saltsof acidic groups such as carboxylic acids. The pharmaceuticallyacceptable salts include the conventional non-toxic salts or thequaternary ammonium salts of the parent compound formed, for example,from non-toxic inorganic or organic acids. For example, suchconventional non-toxic salts include those derived from inorganic acidssuch as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, andnitric; and the salts prepared from organic acids such as acetic,propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric,ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic,benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric,toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, andisethionic, and the like.

The pharmaceutically acceptable salts of the present invention can besynthesized from the parent compound which contains a basic or acidicmoiety by conventional chemical methods. Generally, such salts can beprepared by reacting the free acid or base forms of these compounds witha stoichiometric amount of the appropriate base or acid in water or inan organic solvent, or in a mixture of the two; generally, nonaqueousmedia like ether, ethyl acetate, ethanol, isopropanol, or acetonitrileare preferred. Lists of suitable salts are found in Remington'sPharmaceutical Sciences, 18th ed., Mack Publishing Company, Easton, Pa.,1990, the disclosure of which is hereby incorporated by reference.

In addition, compounds of formula I may have prodrug forms. Any compoundthat will be converted in vivo to provide the bioactive agent (i.e., acompound of formula I) is a prodrug within the scope and spirit of theinvention. Various forms of prodrugs are well known in the art. Forexamples of such prodrug derivatives, see:

-   -   a) Design of prodrugs, edited by H. Bundgaard, (Elsevier, 1985),        and Methods in Enzymology, Vol. 42, at pp. 309-396, edited by K.        Widder, et. al. (Academic Press, 1985);    -   b) A Textbook of Drug Design and Development, edited by        Krosgaard-Larsen and H. Bundgaard, Chapter 5, “Design and        Application of Prodrugs,” by H. Bundgaard, at pp. 113-191        (1991);    -   c) H. Bundgaard, Advanced Drug Delivery Reviews, Vol. 8, p. 1-38        (1992);    -   d) H. Bundgaard, et al., Journal of Pharmaceutical Sciences,        Vol. 77, p. 285 (1988); and    -   e) N. Kakeya, et. al., Chem Phar Bull., Vol. 32, p. 692 (1984).

Compounds containing a carboxy group can form physiologicallyhydrolyzable esters which serve as prodrugs by being hydrolyzed in thebody to yield formula I compounds per se. Such prodrugs are preferablyadministered orally since hydrolysis in many instances occursprincipally under the influence of the digestive enzymes. Parenteraladministration may be used where the ester per se is active, or in thoseinstances where hydrolysis occurs in the blood. Examples ofphysiologically hydrolyzable esters of compounds of formula I includeC₁₋₆alkyl, C₁₋₆alkylbenzyl, 4-methoxybenzyl, indanyl, phthalyl,methoxymethyl, C₁₋₆ alkanoyloxy-C₁₋₆alkyl, e.g. acetoxymethyl,pivaloyloxymethyl or propionyloxymethyl,C₁₋₆alkoxycarbonyloxy-C₁₋₆alkyl, e.g. methoxycarbonyl-oxymethyl orethoxycarbonyloxymethyl, glycyloxymethyl, phenylglycyloxymethyl,(5-methyl-2-oxo-1,3-dioxolen-4-yl)-methyl and other well knownphysiologically hydrolyzable esters used, for example, in the penicillinand cephalosporin arts. Such esters may be prepared by conventionaltechniques known in the art.

Preparation of Prodrugs is Well Known in the Art and Described in, forexample, Medicinal Chemistry: Principles and Practice, ed. F. D. King,The Royal Society of Chemistry, Cambridge, UK, 1994, which isincorporated herein by reference in its entirety.

Isotopically labeled compounds of the present invention, i.e., whereinone or more of the atoms described are replaced by an isotope of thatatom (e.g., C replaced by ¹³C or by ¹⁴C; and isotopes of hydrogeninclude tritium and deuterium), are also provided herein. Such compoundshave a variety of potential uses, e.g., as standards and reagents indetermining the ability of a potential pharmaceutical to bind to targetproteins or receptors, or for imaging compounds of this invention boundto biological receptors in vivo or in vitro.

Compounds of the present invention are, subsequent to their preparation,preferably isolated and purified to obtain a composition containing anamount by weight equal to or greater than 98%, preferably 99%, compoundof the present invention (“substantially pure”), which is then used orformulated as described herein. Such “substantially pure” compounds arealso contemplated herein as part of the present invention.

“Stable compound” and “stable structure” are meant to indicate acompound that is sufficiently robust to survive isolation to a usefuldegree of purity from a reaction mixture, and formulation into anefficacious therapeutic agent. It is preferred that compounds of thepresent invention do not contain a N-halo, S(O)₂H, or S(O)H group.

The term “solvate” means a physical association of a compound of thisinvention with one or more solvent molecules, whether organic orinorganic. This physical association includes hydrogen bonding. Incertain instances the solvate will be capable of isolation, for examplewhen one or more solvent molecules are incorporated in the crystallattice of the crystalline solid. “Solvate” encompasses bothsolution-phase and isolable solvates. Exemplary solvates includehydrates, ethanolates, methanolates, isopropanolates and the like.Methods of solvation are generally known in the art.

As used herein, the term “patient” encompasses all mammalian species.

As used herein, “treating” or “treatment” cover the treatment of adisease-state in a mammal, particularly in a human, and include: (a)preventing the disease-state from occurring in a mammal, in particular,when such mammal is predisposed to the disease-state but has not yetbeen diagnosed as having it; (b) inhibiting the disease-state, i.e.,arresting it development; and/or (c) relieving the disease-state, i.e.,causing regression of the disease state.

“Therapeutically effective amount” is intended to include an amount of acompound of the present invention that is effective when administeredalone or in combination to inhibit factor XIa and/or plasma kallikreinor to treat the disorders listed herein. When applied to a combination,the term refers to combined amounts of the active ingredients thatresult in the therapeutic effect, whether administered in combination,serially or simultaneously. The combination of compounds is preferably asynergistic combination. Synergy, as described, for example, by Chou andTalalay, Adv. Enzyme Regul. 1984, 22:27-55, occurs when the effect (inthis case, prevention of thrombosis) of the compounds when administeredin combination is greater than the additive effect of the compounds whenadministered alone as a single agent. In general, a synergistic effectis most clearly demonstrated at sub-optimal concentrations of thecompounds. Synergy can be in terms of lower cytotoxicity, increasedantithrombotic and/or anti-inflammatory effect, or some other beneficialeffect of the combination compared with the individual components.

The term “pharmaceutical composition” means a composition comprising acompound of the invention in combination with at least one additionalpharmaceutically acceptable carrier. A “pharmaceutically acceptablecarrier” refers to media generally accepted in the art for the deliveryof biologically active agents to animals, in particular, mammals,including, i.e., adjuvant, excipient or vehicle, such as diluents,preserving agents, fillers, flow regulating agents, disintegratingagents, wetting agents, emulsifying agents, suspending agents,sweetening agents, flavoring agents, perfuming agents, antibacterialagents, antifungal agents, lubricating agents and dispensing agents,depending on the nature of the mode of administration and dosage forms.Pharmaceutically acceptable carriers are formulated according to anumber of factors well within the purview of those of ordinary skill inthe art. These include, without limitation: the type and nature of theactive agent being formulated; the subject to which the agent-containingcomposition is to be administered; the intended route of administrationof the composition; and the therapeutic indication being targeted.Pharmaceutically acceptable carriers include both aqueous andnon-aqueous liquid media, as well as a variety of solid and semi-soliddosage forms. Such carriers can include a number of differentingredients and additives in addition to the active agent, suchadditional ingredients being included in the formulation for a varietyof reasons, e.g., stabilization of the active agent, binders, etc., wellknown to those of ordinary skill in the art. Descriptions of suitablepharmaceutically acceptable carriers, and factors involved in theirselection, are found in a variety of readily available sources such as,for example, Remington's Pharmaceutical Sciences, 18th ed., 1990, whichis incorporated herein by reference in its entirety.

Abbreviations as used herein, are defined as follows: “1×” for once,“2×” for twice, “3×” for thrice, “C” for degrees Celsius, “eq” forequivalent or equivalents, “g” for gram or grams, “mg” for milligram ormilligrams, “L” for liter or liters, “mL” for milliliter or milliliters,“μL” for microliter or microliters, “N” for normal, “M” for molar,“mmol” for millimole or millimoles, “min” for minute or minutes, “h” forhour or hours, “rt” for room temperature, “RT” for retention time, “atm”for atmosphere, “psi” for pounds per square inch, “conc.” forconcentrate, “sat” or “sat'd” for saturated, “MW” for molecular weight,“mp” for melting point, “MS” or “Mass Spec” for mass spectrometry, “ESI”for electrospray ionization mass spectroscopy, “HR” for high resolution,“HRMS” for high resolution mass spectrometry, “LC-MS” for liquidchromatography mass spectrometry, “HPLC” for high pressure liquidchromatography, “RP HPLC” for reverse phase HPLC, “TLC” for thin layerchromatography, “NMR” for nuclear magnetic resonance spectroscopy, “¹H”for proton, “δ” for delta, “s” for singlet, “d” for doublet, “t” fortriplet, “q” for quartet, “m” for multiplet, “br” for broad, “Hz” forhertz, and “tlc” for thin layer chromatography. “α”, “β”, “R”, “S”, “E”,and “Z” are stereochemical designations familiar to one skilled in theart.

-   -   Me methyl    -   Et ethyl    -   MeOH methanol    -   EtOH ethanol    -   EtOAc ethyl acetate    -   Ph phenyl    -   Bn benzyl    -   t-Bu tertiary butyl    -   ACN or CH₃CN acetonitrile    -   BOP reagent benzotriazol-1-yloxytris(dimethylamino)phosphonium        hexafluorophosphate    -   Boc tert-butyloxycarbonyl    -   cDNA complimentary DNA    -   CH₂Cl₂ dichloromethane    -   Cs₂CO₃ cesium carbonate    -   DCM dichloromethane    -   DCC dicyclohexylcarbodiimide    -   DIBAL-H diisobutylaluminum hydride    -   DIEA or DIPEA N,N,-diisopropylethylamine    -   DMAP 4-dimethylamino-pyridine    -   DMEM Dulbecco's modified Eagle media    -   DMF dimethyl formamide    -   DMSO dimethyl sulfoxide    -   EDC (or EDC.HCl) or EDCI (or EDCI.HCl) or EDAC        3-ethyl-3′-(dimethylamino)propyl-carbodiimide hydrochloride (or        1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride)    -   EDTA ethylenediaminetetraacetic acid    -   FBS Fetal Bovine Serum    -   HCl hydrochloric acid    -   HEPES 4-(2-hydroxyethyl)piperaxine-1-ethanesulfonic acid    -   Hex hexane    -   HOBt 1-hydroxybenzotriaole hydrate    -   Hunig's base N,N-diisopropylethyl amine    -   LiHMDS Lithium bis(trimethylsilyl amide)    -   NBS N-bromosuccinimide    -   D-PBS Dulbecco's Phosphate Buffered Saline    -   TFA trifluoroacetic acid    -   THF tetrahydrofuran    -   TRIS tris(hydroxymethyl)aminomethane    -   K₃PO₄ potassium phosphate    -   LiHMDS lithium hexamethyldisilazide    -   MgSO₄ magnesium sulfate    -   Na₂SO₄ sodium sulfate    -   Pd₂(dba)₃ tris(dibenzylideneacetone)dipalladium (0)    -   Pd(dppf)Cl₂.CH₂Cl_(2 [)1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II),        complex with dichloromethane    -   Pd(Ph₃P)₄ tetrakis(triphenylphosphine) palladium (0)        Synthesis

The compounds of the present invention can be prepared in a number ofways known to one skilled in the art of organic synthesis. The compoundsof the present invention can be synthesized using the methods describedbelow, together with synthetic methods known in the art of syntheticorganic chemistry, or by variations thereon as appreciated by thoseskilled in the art. Preferred methods include, but are not limited to,those described below. The reactions are performed in a solventappropriate to the reagents and materials employed and suitable for thetransformations being effected. It will be understood by those skilledin the art of organic synthesis that the functionality present on themolecule should be consistent with the transformations proposed. Thiswill sometimes require a judgment to modify the order of the syntheticsteps or to select one particular process scheme over another in orderto obtain a desired compound of the invention. Also, in the descriptionof the synthetic methods described below, it is to be understood thatall proposed reaction conditions, including choice of solvent, reactionatmosphere, reaction temperature, duration of the experiment and workupprocedures, are chosen to be the conditions standard for that reaction,which should be readily recognized by one skilled in the art. It isunderstood by one skilled in the art of organic synthesis that thefunctionality present on various portions of the molecule must becompatible with the reagents and reactions proposed. Such restrictionsto the substituents that are compatible with the reaction conditionswill be readily apparent to one skilled in the art and alternate methodsmust then be used.

It will also be recognized that another major consideration in theplanning of any synthetic route in this field is the judicious choice ofthe protecting group used for protection of the reactive functionalgroups present in the compounds described in this invention. Anauthoritative account describing the many alternatives to the trainedpractitioner is Greene and Wuts (Protective Groups In Organic Synthesis,Wiley-Interscience, 3^(rd) Edition, 1999).

All references cited herein are hereby incorporated in their entiretyherein by reference.

Representative thiophene compounds of this invention can be prepared asshown in Scheme 1. Using a modified procedure from Hart, et al. (J. Org.Chem., 1983, 48(3), 289-294), in situ generation ofN-trimethylsilylaldimines from appropriately substitutedthiophenaldehydes (1a) and lithium bis(trimethylsilyl)amide, followed bythe addition of Grignard or alkyllithium reagents (1b), gives, afteraqueous workup, the primary amine 1c. Amide coupling between 1c andappropriately substituted carboxylic acids (1d) employing suitablecoupling reagents, such as EDCI, HOBt, and base, generates 1e (for othersuitable coupling conditions see Han, S—Y, et al. Tetrahedron, 2004, 60,2447). Suzuki coupling between 1e and an appropriately substituted arylor heteroaryl boronic acid or ester 1f in the presence of a base such asanhydrous potassium phosphate, cesium carbonate or aqueous sodiumcarbonate, in a solvent such as DMSO, dioxane, or toluene, using acatalyst such as Pd₂(dba)₃/tri-t-butylphosphonium tetrafluoroborate,Pd(Ph₃P)₄, or Pd(dppf)Cl₂.CH₂Cl₂, provides the compounds of the presentinvention of formula 1g.

Alternately, compounds of this invention can be prepared as described inScheme 2, wherein a Suzuki coupling between appropriately substitutedaldehydes 1a and an appropriately substituted aryl or heteroaryl boronicacid or ester 1f, using conditions described above for the conversion of1e to 1g, provides compounds of formula 2a, which can be converted toprimary amines 2b using the methods described for the conversion of 1ato 1c above. Amide coupling between 2b and appropriately substitutedcarboxylic acids (1d) employing suitable coupling reagents, aspreviously described for the conversion of 1c to 1e, generates compoundsof formula 1g. It is also understood that further manipulation offunctional groups on R³R⁴, and A using methods known to one skilled inthe art of organic synthesis provides additional compounds of thisinvention. Further manipulation of functional groups on R³ and R⁴ can befound in U.S. application Ser. No. 11/151,667.

Representative thiophene compounds of this invention wherein R¹¹ is—(CH₂)_(n)C(O)NR⁷R⁸ can be prepared as shown in Scheme 3. Followingprotection of amino acid 3a with di-tert-butyl dicarbonate, the acidmoiety can be coupled with an appropriately substituted amine (3b)employing suitable coupling reagents, as previously described for theconversion of 1c to 1e, to give amide 3c. Deprotection with TFA andcoupling of the resulting amine with appropriately substitutedcarboxylic acids (1d) employing suitable coupling reagents as previouslydescribed for the conversion of 1c to 1e, gives 3d. Suzuki couplingbetween 3d and an appropriately substituted aryl or heteroaryl boronicacid or ester 1f using conditions described above for the conversion of1e to 1g provides the biaryl compound 3e. Further manipulation offunctional groups on R³ and R⁴ using methods known to one skilled in theart of organic synthesis will give additional compounds of theinvention.

In cases where suitably substituted aldehydes are not commerciallyavailable, additional aldehydes useful for the synthesis of compounds inScheme 1 and 2 are accessible via a variety of straightforward chemicaltransformations known to one skilled in the art. As outlined in Scheme4, aldehydes 4c suitable for use in preparing compounds of thisinvention may be obtained through oxidation of the correspondingalcohols or halides 4a as taught in “Advanced Organic Chemistry” (JerryMarch, Wiley Interscience, 4^(th) Edition). Alternatively, suitablealdehydes may be prepared by hydrogenation of the correspondingcarboxylic acids 4b in the presence of palladium complexes and pivalicanhydride or by reduction of the corresponding carboxylic acids 4b withborane followed by oxidation of the intermediate alcohol with manganesedioxide or Dess-Martin periodinane. In addition, the ester (4b; R=alkyl)can be reduced with DIBAL-H (Chandrasekhar, et al. Tetrahedron Letters1998, 39, 909-910) to give the aldehyde 4c. Additional aryl aldehydesmay be obtained from the corresponding methyl derivatives 4d by directoxidation or by a two-step procedure which involves formation of thedibromide intermediate and subsequent conversion to the aldehyde with asilver salt, hexamethylenetetramine, or morpholine (Demir, A. S.; Reis,O. Tetrahedron, 2004, 60, 3803; Tidwell, R. R.; et al. J. Med. Chem.,1978, 21(7), 613; Polniaszek, R. P. et al. WO 02/32884). Additionalsuitable aldehydes may be prepared through formylation of the aromaticring of 4e as taught in “Advanced Organic Chemistry” (Jerry March, WileyInterscience, 4^(th) Edition, pg 542-546 and references therein).

A suitably substituted carboxylic acid (A-CO₂H, 1d) is used in the amidecouplings shown in Scheme 1-3. Many of these carboxylic acids arecommercially available. In cases where the carboxylic acids are notcommercially available, they can be prepared using methods known to oneskilled in the art (Scheme 5A). Carboxylic acids suitable for use inpreparing compounds of this invention may be obtained through oxidationof the corresponding alcohol 5a or aldehyde 5b as taught in “AdvancedOrganic Chemistry” (Jerry March, Wiley Interscience, 4^(th) Edition, pg1196 and 701-703 and references therein). Alternately, oxidation of themethyl side chain in 5c gives aromatic carboxylic acids as taught in“Advanced Organic Chemistry” (Jerry March, Wiley Interscience, 4^(th)Edition, pg 1183-1184 and references therein). Hydrolysis of esters 5dor nitriles 5e yields the carboxylic acid as taught in “Advanced OrganicChemistry” (Jerry March, Wiley Interscience, 4^(th) Edition, pg 378-383and 887-889 and references therein). Alternately, carbonylation ofbromide 5f gives the carboxylic acid as taught in “Advanced OrganicChemistry” (Jerry March, Wiley Interscience, 4^(th) Edition, pg 484-486,546-547, and 664-665 and references therein). The R¹ and R² groups on Acan be further manipulated using methods known to one skilled in the artto provide additional compounds of this invention. For example, when R¹is a cyano group, it can be reduced to —CH₂NH₂ with a suitable reducingagent. The cyano group can also be converted to an amidine by reactionwith hydroxylamine followed hydrogenolysis with a palladium catalystunder a hydrogen atmosphere or via a Pinner reaction followed byammonolysis.

Additional substituted carboxylic acids (A-(CH₂)₂CO₂H) 5f are eithercommercially available, or they can be prepared from the correspondingbromides, alcohols, aldehydes, or esters as shown in Scheme 5B usingmethods known to one skilled in the art.

Additional carboxylic acid intermediates of formulae 5k, 5l, 5m, and 5nuseful for preparation of amide compounds of this invention can beprepared as outlined in Schemes 5C and 5D.

In cases where suitably substituted boronic acids used in Schemes 1 and2 above are not commercially available, the corresponding4,4,5,5-tetramethyl-[1,3,2]dioxaborolane intermediate may be accessedvia a modified procedure of Ishiyama, T. et al. (J. Org. Chem. 1995,60(23), 7508-7510) wherein an aryl halide is subjected to a palladiummediated coupling with a diboron species such as bis(pinacolato)diboron. Alternately, this same intermediate can be prepared by reactionof the aryl halide with the corresponding dialkoxyhydroborane asdescribed by Murata, et al. (J. Org. Chem. 1997, 62(19), 6458-6459).Boron pinacolate intermediates can be used in place of boronic acids forcoupling to aryl halides or triflates. Alternately, the correspondingboronic acids can be prepared by metal-halogen exchange of aryl halidesfollowed by quenching with a trialkoxyborate reagent and aqueous workupto provide the boronic acid (Miyaura, N.; Suzuki, A. Chem. Review, 1995,95, 2457).

It is also realized that the scope of intermediate synthesis can befurther extended outside the use of Suzuki methodology since theprecursor aryl halides or triflates described above are also precursorsfor Stille, Negishi, Hiyama, and Kumada-type cross couplingmethodologies (Tsuji, J. Transition Metal Reagents and Catalysts:Innovations in Organic Synthesis, John Wiley & Sons, 2000; Tsuji, J.Palladium Reagents and Catalysts: Innovations in Organic Synthesis, JohnWiley & Sons, 1996.)

The synthesis of a specific example of a compound of this invention isdepicted in Scheme 8. In situ generation of the N-trimethylsilylaldiminefrom aldehyde 8a and lithium bis(trimethylsilyl)amide, followed by theaddition of benzylmagnesium chloride, gives, after aqueous workup, theprimary amine 8b. Amide coupling between 8b and Boc-tranexamic acidemploying EDCI, HOBt, and base in DMF solvent generates 8c. Suzukicoupling between 8c and 4-carbamoylphenylboronic acid provides 8d.Chlorination of 8d with NCS followed by removal of the Boc protectinggroup using TFA yields a compound of this invention of formula 8e.

Compounds of this invention wherein L₁ is —CH₂NH— can be prepared asoutlined in Scheme 9. Condensation of an appropriately functionalizedamine intermediate 9a with a suitably substituted benzylisocyanate 9b ina solvent such as tetrahydrofuran or methylene chloride in the presenceof a base such as triethylamine, diisopropylethylamine or potassiumcarbonate provides ureas of formula 9c. Alternatively, ureas of formula9c of this invention can be prepared by condensation of an amineintermediate 9a with carbonyl diimidazole in a solvent such astetrahydrofuran or N,N-dimethylformamide followed by treatment of theintermediate imidazole carboxamide in situ with an suitably substitutedbenzyl amine 9d. Urea linked compounds of this invention of formula 9ccan also be prepared by condensation of amine intermediate 9a withp-nitrophenylchloroformate in the presence of a suitable base, such astriethylamine, followed by treatment of the resultingp-nitrophenylcarbamate with an appropriately substituted amine 9d.

Isocyanates of formula 9b used in Scheme 1 above are either commerciallyavailable or can be readily prepared from the corresponding amines 9d bytreatment with phosgene or by various other methods known in the art(see for example, H. Eckert & B. Forster, Angew. Chem. Int. Ed. 1987,26, 894; H. Knolker & T. Braxmeier, Synlett, 1997, 925; S. Porwanski etal. Tetrahedron Lett. 2004, 45, 5027). Amines of formula 9d are alsoavailable commercially or can be prepared by those knowledgeable in theart from a variety of easily accessible starting materials such asnitrites, aldehydes, alcohols, halides, acids and esters by methodsincluding, but not limited to, those outlined in Scheme 10.

Compounds of this invention wherein L₁ is —NHNH— of formula 11c can besynthesized similarly as outlined in Scheme 10 by treatment of asuitably functionalized amine intermediate 9a with p-nitrochloroformateas described above followed by treatment of the resultingp-nitrophenylcarbamate ha with a suitably substituted hydrazine offormula 11b.

Hydrazine reagents of formula 11b used to prepare compounds of thisinvention in Scheme 11 are commercially available or can be prepared bythose knowledgeable in the art of organic synthesis by other methods.For example, when A is an aryl or heteroaryl group, the requisitehydrazine reagent is readily available via diazotization of a startingaryl or heteroarylamine 12a followed by reduction of the resultingdiazonium salt with tin chloride to the corresponding arylhydrazine 12bas illustrated in Scheme 12.

Compounds of this invention, wherein L₁ is —CH₂CH₂—, —CH═CH—, —C≡C—,—OCH₂—, or —SCH₂—, can be obtained by the condensation of the amineintermediate 9a shown in Scheme 9 with appropriately substitutedcarboxylic acid chlorides, mixed carboxylic acid anhydrides orcarboxylic acids using standard amide bond forming conditions known toone skilled in the art. Reagent combinations which may be employed forthe coupling of amines of formula 9a with suitably substitutedcarboxylic acids include, but are not limited to: BOP-reagent andtriethylamine, EDCI, HOBt, and N-methylmorpholine, or HATU and Hunig'sbase (DIPEA). Solvents suitable for this transformation include, but arenot limited to, tetrahydrofuran and dimethylformamide. Coupling ofamines of formula 9a with suitably substituted carboxylic acid chloridesor mixed anhydrides can be carried out in solvents such as methylenechloride or tetrahydrofuran in the presence of a base such astriethylamine, N,N-dimethyaminopyridine (DMAP) or potassium carbonate.Suitably substituted carboxylic acids are either commercially available,or they can be prepared as shown in Schemes 5B-5D above using methodsknown to one skilled in the art.

Compounds of this invention where R³ is a 4-aminoquinazoline,3-aminoindazole or 3-aminobenzisoxazole group can be prepared from acommon thiophene precursor 11a bearing an ortho fluorobenzonitrilesubstituent as shown in Scheme 11. Amino-indazole compounds 11b areobtained by heating 11a with hydrazine or hydrazine monohydrate in asuitable solvent, such as n-butanol or ethanol either conventionally orvia microwave irradiation at a temperature between 80 and 160° C. Theaminoquinazoline 11c may be prepared by combining 11a with formamidineacetate, or other suitable salt forms, in a suitable solvent such asdimethyl acetamide or dimethyl formamide, and heating to approximately140° C. Similarly the aminobenzisoxazoles 11d may be prepared fromfluorobenzonitrile precursor 11a by treatment with acetoxyhydroxamicacid in the presence of a base such as potassium carbonate in a suitablesolvent such as wet DMF.

The compound of the instant invention herein described may haveasymmetric center(s). For example, the chiral carbon atom in Formula (I)as indicated below, exists in either as S or R configuration.

For example, but not limited to therein, in compounds of Formula (I),the following two stereoisomeric configurations are possible:

They are collectively, as well as individually, considered part of theinvention. In a preferred stereoisomeric embodiment the presentinvention provides for a stereoisomeric configuration of isomer-1 forFormula (I) or tautomer, pharmaceutically acceptable salt, solvate, orprodrug form thereof.

Other features of the invention will become apparent in the course ofthe following descriptions of exemplary embodiments that are given forillustration of the invention and are not intended to be limitingthereof.

The following Examples have been prepared, isolated and characterizedusing the methods disclosed herein. The following Examples demonstrate apartial scope of the invention and are not meant to be limiting of thescope of the invention.

In the following experimental procedures, solution ratios express avolume relationship, unless stated otherwise. NMR chemical shifts (δ)are reported in parts per million (ppm). Products were analyzed byreverse phase analytical HPLC carried out on a Shimadzu Analytical HPLCsystem running DiscoveryVP software using Method A: Phenomenex Luna C18column (4.6×50 mm or 4.6×75 mm) eluted at 4 mL/min with a 2, 4 or 8 mingradient from 100% A to 100% B (A: 10% methanol, 89.9% water, 0.1% TFA;B: 10% water, 89.9% methanol, 0.1% TFA, UV 220 nm), or Method B:Phenomenex Luna C18 column (4.6×50 mm) eluted at 4 mL/min with a 4 mingradient from 100% A to 100% B (A: 10% acetonitrile, 89.9% water, 0.1%TFA; B: 10% water, 89.9% acetonitrile, 0.1% TFA, UV 220 nm).Purification of intermediates and final products was carried out viaeither normal or reverse phase chromatography. Normal phasechromatography was carried out on an ISCO CombiFlash™ System usingprepacked SiO₂ cartridges eluted with gradients of hexanes and ethylacetate or methylene chloride and methanol. Reverse phase preparativeHPLC was carried out using a Shimadzu Preparative HPLC system runningDiscoveryVP software using Method A: YMC Sunfire 5 μm C18 30×100 mmcolumn with a 10 min gradient at 40 mL/min from 100% A to 100% B (A: 10%methanol, 89.9% water, 0.1% TFA; B: 10% water, 89.9% methanol, 0.1% TFA,UV 220 nm), Method B: Phenomenex AXIA Luna 5 μm C18 30×75 mm column witha 10 min gradient at 40 mL/min from 100% A to 100% B (A: 10%acetonitrile, 89.9% water, 0.1% TFA; B: 10% water, 89.9% acetonitrile,0.1% TFA, UV 220 nm), Method C: Phenomenex Luna 5 μm C18 30×100 mmcolumn with a 10 min gradient at 40 mL/min from 100% A to 100% B (A: 10%acetonitrile, 89.9% water, 0.1% TFA; B: 10% water, 89.9% acetonitrile,0.1% TFA, UV 220 nm), or Method D: Phenomenex Luna 5 μm C18 30×100 mmcolumn with a 10 min gradient at 40 mL/min from 100% A to 100% B (A: 10%methanol, 89.9% water, 0.1% TFA; B: 10% water, 89.9% methanol, 0.1% TFA,UV 220 nm). Alternatively, reverse phase preparative HPLC was carriedout using a Varian ProStar Preparative HPLC System running Star 6.2Chromatography Workstation software using Method E: Dynamax 10 μm C1841.4×250 mm column with a 30 min gradient at 30 mL/min from 10% B to100% B (A 98% water, 2% acetonitrile, 0.05% TFA; B: 98% acetonitrile, 2%water, 0.05% TFA, UV 254 nm). LCMS chromatograms were obtained on aShimadzu HPLC system running DiscoveryVP software, coupled with a WatersZQ mass spectrometer running MassLynx version 3.5 software using thesame columns and conditions as utilized for analytical described above.

EXAMPLES Example 14-(5-{1-[(Trans-4-aminomethyl-cyclohexanecarbonyl)-amino]-2-phenyl-ethyl}-2-chloro-thiophen-3-yl)-benzamide,trifluoroacetic acid salt 1A.1-(4-Bromothiophen-2-yl)-2-phenylethanamine

To a solution of 4-bromothiophene-2-carboxaldehyde (10.1 g, 52.8 mmol)in anhydrous THF (150 mL) at 0° C. under N2 was added dropwise 1.0 MLiHMDS (58 mL) in THF. After 30 min, a solution of 2.0 M benzylmagnesiumchloride (27 mL) in THF was added dropwise. The resulting mixture wasstirred at rt for 50 min. The reaction mixture was quenched with sat.NH₄Cl and most of the THF was evaporated. The residue was diluted withethyl acetate (150 mL), washed with water and brine, and dried overMgSO₄. Purification by flash chromatography gave 1A as a light yellowoil. ¹H NMR (400 MHz, CDCl₃) δ: 1.5 (s, broad, 2H), 2.8 (m, 1H), 3.08(m, 1H), 4.4 (m, 1H), 6.8 (s, 1H), 7.1-7.3 (m, 6H).

1B.Trans-{4-[1-(4-bromo-thiophen-2-yl)-2-phenylethylcarbamoyl]-cyclohexylmethyl}-carbamicacid tert-butyl ester

At 0° C. under N₂, diisopropylethylamine (1.1 mL, 6.6 mmol) was addeddropwise to a mixture of 1A (564 mg, 2.0 mmol), Boc-tranexamic acid (565mg, 2.2 mmol), HOBt (297 mg, 2.2 mmol), and EDCI (422 mg, 2.2 mmol) inanhydrous DMF (15 mL). After addition, the mixture was slowly warmed tort and stirred for 2 h. The reaction mixture was diluted with ethylacetate, washed with water, 1.0 N HCl, sat. NaHCO₃, and brine, driedover MgSO₄, filtered, and concentrated. Chromatography on silica gelprovided 1B as a light yellow solid. LC/MS m/z 521.1 (M+H)⁺. ¹H NMR (400MHz, CDCl₃) δ: 0.8-0-1.0 (m, 2H), 1.45 (s, 9H), 1.25-1.45 (m, 2H),1.70-1.85 (m, 2H), 1.90-2.05 (2H), 2.95 (2H), 3.05-3.25 (2H), 4.60 (s,broad, 1H), 5.55 (m, 1H), 5.75 (m, 1H), 6.8 (s, 1H), 7.1 (s, 1H), 7.15(d, J=7.8 Hz, 2H), 7.2-7.35, (m, 3H).

1C.Trans-(4-{1-[4-(4-carbamoyl-phenyl)-thiophen-2-yl]-2-phenyl-ethylcarbamoyl}-cyclohexylmethyl)-carbamicacid tert-butyl ester

A mixture of 1B (522 mg, 1.0 mmol) and 4-carbamoylphenylboronic acid(248 mg, 1.5 mmol) was dissolved in DMF (15 mL). Under N₂, potassiumphosphate (530 mg, 2.5 mmol) and bis(tri-t-butylphosphine) palladium (25mg, 5 mol %) were added to the mixture. The resulting mixture wasstirred at 85° C. for 2.5 h. The reaction mixture was cooled to rt,filtered and concentrated. Reverse-phase HPLC purification afforded ICas a light yellow solid. LC/MS m/z 561.2 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD)δ: 0.91-0.95 (m, 2H), 1.29-1.42 (m, 4H), 1.55-1.63, (m, 1H), 1.75-1.78(m, 2H), 1.98-2.09 (m, 1H), 2.85 (d, J=7.9 Hz, 2H), 3.30-3.33 (m, 2H),5.45-5.48 (m, 1H), 7.19-7.20 (m, 1H), 7.25, (s, 4H), 7.35 (s, 1H), 7.61(s, 1H), 7.69 (d, J=7.6 Hz, 2H), 7.87 (d, J=7.6 Hz, 2H), 7.97 (s, 1H),8.41 (m, 1H).

1D.(Trans-4-{1-[4-(4-carbamoyl-phenyl)-5-chloro-thiophen-2-yl]-2-phenyl-ethylcarbamoyl}-cyclohexylmethyl)-carbamicacid tert-butyl ester

A mixture of 1C (336 mg, 0.6 mmol) and NCS (104 mg, 0.78 mmol) inchloroform (20 mL) was stirred at 60° C. under N₂. After 1.5 h, themixture was cooled to rt and concentrated. Reverse-phase HPLCpurification gave ID as a light yellow solid. LC/MS m/z 596.2 (M+H)⁺.

1E: Example 1

To a solution of ID (60 mg, 0.1 mmol) in methylene chloride (5.0 mL) atrt under N₂ was added TFA (2.5 mL). After 1.5 h, the mixture wasconcentrated and purified by reverse-phase HPLC to give Example 1 as awhite solid. LC/MS m/z 496.2 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD): δ0.90-0.98 (m, 2H), 1.28-1.61 (m, 3H), 1.75-1.87 (m, 4H), 2.09-2.18 (m,1H), 2.64 (d, J=7.3 Hz, 2H), 3.01-3.30 (dm, J=13.5 Hz, 2H), 5.35-5.41(m, 1H), 5.44 (br, 2H), 6.78 (s, 1H), 7.12-7.15 (m, 5H), 7.51 (d, J=7.6Hz, 2H), 7.63 (br, 2H), 7.78 (d, J=7.6 Hz, 2H).

Example 2 Trans-4-aminomethyl-cyclohexanecarboxylic acid{1-[4-(3-amino-1H-indazol-6-yl)-5-chloro-thiophen-2-yl]-2-phenyl-ethyl}-amide,trifluoroacetic acid salt 2A. Trans-4-aminomethyl-cyclohexanecarboxylicacid{1-[5-chloro-4-(4-cyano-3-fluoro-phenyl)-thiophen-2-yl]-2-phenyl-ethyl}-amide,trifluoroacetic acid salt

Following procedures similar to 1A-1E using commercially available4-cyano-3-fluorophenylboronic acid in place of 4-carbamoylphenyl boronicacid, 2A was obtained as a light yellow solid. LC/MS m/z 496.1 (M+H)⁺.

2B. Example 2

A mixture of 2A (59 mg, 0.1 mmol) and excess hydrazine (10 eq) in n-BuOHwas stirred at 120° C. under N₂. After 2 h, the mixture was cooled to rtand concentrated to dryness. This mixture was then treated with 1:1TFA/CH₂Cl₂ (10 mL). After reverse-phase HPLC purification, Example 2 wasobtained as a light yellow solid. LC/MS m/z 508.2 (M+H)⁺. ¹H NMR (400MHz, CD₃OD): δ 0.81-0.97 (m, 2H), 1.22-1.58 (m, 3H), 1.71-1.80 (m, 4H),2.05 (m, 1H), 2.67 (d, J=7.6 Hz, 2H), 3.01-3.3.18 (dm, J=13.6 Hz, 2H),5.28 (m, 1H), 5.49 (br, 2H), 6.91 (s, 1H), 7.18 (m, 5H), 7.25 (d, J=7.5Hz, 1H), 7.45 (s, 1H), 7.83 (d, J=7.5 Hz, 1H), 8.42 (br, 2H).

Example 4 Trans-4-aminomethyl-cyclohexanecarboxylic acid{1-[4-(3-amino-1H-indazol-6-yl)-thiophen-2-yl]-2-phenyl-ethyl}-amide,trifluoroacetic acid salt

Example 4 was prepared by procedures similar to Example 2, omitting thechlorination step. LC/MS m/z 474.3 (M+H)⁺.

Example 53-(5-{1-[(Trans-4-aminomethyl-cyclohexanecarbonyl)-amino]-2-phenyl-ethyl}-2-chloro-thiophen-3-yl)-benzoicacid, trifluoroacetic acid salt

Example 5 was prepared following procedures similar to 1A-1E usingcommercially available 3-boronobenzoic acid in place of4-carbamoylphenyl boronic acid. LC/MS m/z 497.2 (M+H)⁺. ¹H NMR (400 MHz,CD₃OD): δ 0.91-1.08 (m, 2H), 1.29-1.58 (m, 3H), 1.79-1.88 (m, 4H), 2.05(m, 1H), 2.76 (d, J=7.4 Hz, 2H), 3.11-3.18 (dm, J=13.5 Hz, 2H), 5.38 (m,1H), 6.97 (s, 1H), 7.19 (m, 5H), 7.53 (m, 1H), 7.75 (d, J=7.3 Hz, 1H),8.01 (d, J=7.3 Hz, 1H), 8.18 (s, 1H), 8.49, (br, 2H), 9.01 (br, 1H).

Example 64-(5-{1-[(Trans-4-aminomethyl-cyclohexanecarbonyl)-amino]-2-phenyl-ethyl}-2-chloro-thiophen-3-yl)-benzoicacid, trifluoroacetic acid salt

Example 6 was prepared following procedures similar to 1A-1E usingcommercially available 4-boronobenzoic acid in place of4-carbamoylphenyl boronic acid. LC/MS m/z 497.2 (M+H)⁺. ¹H NMR (400 MHz,CD₃OD): δ 0.85-0.98 (m, 2H), 1.19-1.49 (m, 3H), 1.72-1.81 (m, 4H), 2.01(m, 1H), 2.68 (d, J=7.4 Hz, 2H), 2.95-3.11 (dm, J=13.5 Hz, 2H), 5.29 (m,1H), 6.02 (br, 2H), 6.78 (s, 1H), 7.15 (m, 5H), 7.18 (d, J=7.4 Hz, 2H),7.93 (d, J=7.4 Hz, 2H), 8.43 (br, 2H), 9.12 (br, 1H).

Example 7[4-(5-{1-[(Trans-4-Aminomethyl-cyclohexanecarbonyl)-amino]-2-phenyl-ethyl}-2-chloro-thiophen-3-yl)-phenyl]-carbamicacid methyl ester, trifluoroacetic acid salt

Example 7 was prepared similar to Example 1, using commerciallyavailable 4-(methoxycarbonylamino)benzeneboronic acid in place of4-carbamoylphenyl boronic acid. LC/MS m/z 526.2 (M+H)⁺. ¹H NMR (400 MHz,CD₃OD): δ 0.95-1.06 (m, 2H), 1.22-1.59 (m, 3H), 1.72-1.88 (m, 4H), 2.11(m, 1H), 2.74 (d, J=7.4 Hz, 2H), 3.02-3.21 (dm, J=13.5 Hz, 2H), 3.29 (s,3H), 5.31 (m, 1H), 6.89 (s, 1H), 7.18 (d, J=7.5 Hz, 2H), 7.21 (m, 5H),7.35 (d, J=7.5 Hz, 2H), 8.46 (m, 2H).

Example 8(4-{5-[(S)-1-(2,6-Difluoro-4-methoxy-benzoylamino)-2-phenyl-ethyl]-thiophen-3-yl}-phenyl)-carbamicacid methyl ester 8A. tert-Butyl1-(4-bromothiophen-2-yl)-2-phenylethylcarbamate

A mixture of di-tert-butyl dicarbonate (140 mg, 0.64 mmol) and 1A (180mg, 0.64 mmol) in 1N NaOH (20 mL) and MeOH (3 mL) was stirred at rt for2 h. After aqueous workup, purification of the crude product by flashchromatography gave 8A as white solid. LC/MS m/z 765.0 (2M+H)⁺. ¹H NMR(400 MHz, CDCl₃) δ ppm 1.26 (s, 9H), 3.05-3.15 (m, 2H), 4.87 (d, J=8.35,1H), 5.17 (br, 1H), 6.78 (s, 1H), 7.08 (s, 1H), 7.14 (d, J=7.91 Hz, 2H),7.24-7.35 (m, 3H).

8B.{4-[5-(1-tert-Butoxycarbonylamino-2-phenyl-ethyl)-thiophen-3-yl]-phenyl}-carbamicacid methyl ester

A mixture of 7A (111 mg, 0.290 mmol),4-(methoxycarbonylamino)phenylboronic acid (85 mg, 0.436 mmol), andK₃PO₄ (123 mg, 0.581 mmol) was suspended in DMF. To this mixture underN₂ was added Pd(tBu₃P)₂ (14.84 mg, 0.029 mmol) and the resulting mixturewas stirred at 90° C. under N₂ for 2 h. The mixture was cooled to rt,filtered, and concentrated. The residue was dissolved in MeOH (3 mL) andpurified by reverse-phase HPLC. Evaporation of solvent yielded thedesired product as white solid. LC/MS m/z 905.2 (2M+H)⁺. ¹H NMR (400MHz, CD₃OD) δ ppm 1.36 (s, 9H), 3.05-3.25 (m, 2H), 3.73 (s, 3H), 5.07(d, J=6.15 Hz, 1H), 7.15-7.25 (m, 6H), 7.36 (s, 1H), 7.42-7.51 (m, 4H).

8C. Example 8

8B (113 mg, 0.25 mmol) was treated with 4N HCl in dioxane at rt for 1 hto remove the Boc protecting group. The mixture was concentrated anddried under vacuum. To a mixture of this intermediate (88 mg, 0.25mmol), 2,6-difluoro-4-methoxybenzoic acid (52 mg, 0.27 mmol), and EDC(53 mg, 0.27 mmol) in DMF (10 mL) was added dropwise DIEA (2.0 mL). Theresulting mixture was stirred at rt for 4 h, then evaporated. Theresidue was diluted with ethyl acetate, then washed with water, 1 N HCl,and brine. Purification by flash chromatography gave the title compoundas a white solid. LC/MS m/z 523.1 (M+H)⁺. ¹H NMR (400 MHz, CD₃OD): δ3.92 (d, J=6.59 Hz, 2H), 3.77 (s, 3H), 3.79 (s, 3H), 5.77 (q, J=7.32 Hz,1H), 6.25 (d, J=7.91 Hz, 1H), 6.43 (d, J=10.11 Hz, 2H), 6.62 (s, 1H),7.15-7.27 (m, 5H), 7.36-7.46 (m, 4H).

Table 1 below summarizes representative examples of the compounds in thepresent invention synthesized as described above.

TABLE 1 Ex. No. Structure (M + H)⁺ 1

496.2 2

508.2 4

474.3 5

497.2 6

497.2 7

526.2 8

523.1Utility

The compounds of this invention are inhibitors of factor XIa and areuseful as anticoagulants for the treatment or prevention ofthromboembolic disorders in mammals (i.e., factor XIa-associateddisorders). In general, a thromboembolic disorder is a circulatorydisease caused by blood clots (i.e., diseases involving fibrinformation, platelet activation, and/or platelet aggregation). The term“thromboembolic disorders” as used herein includes arterialcardiovascular thromboembolic disorders, venous cardiovascular orcerebrovascular thromboembolic disorders, and thromboembolic disordersin the chambers of the heart or in the peripheral circulation. The term“thromboembolic disorders” as used herein also includes specificdisorders selected from, but not limited to, unstable angina or otheracute coronary syndromes, atrial fibrillation, first or recurrentmyocardial infarction, ischemic sudden death, transient ischemic attack,stroke, atherosclerosis, peripheral occlusive arterial disease, venousthrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism,coronary arterial thrombosis, cerebral arterial thrombosis, cerebralembolism, kidney embolism, pulmonary embolism, and thrombosis resultingfrom medical implants, devices, or procedures in which blood is exposedto an artificial surface that promotes thrombosis. The medical implantsor devices include, but are not limited to: prosthetic valves,artificial valves, indwelling catheters, stents, blood oxygenators,shunts, vascular access ports, ventricular assist devices and artificialhearts or heart chambers, and vessel grafts. The procedures include, butare not limited to: cardiopulmonary bypass, percutaneous coronaryintervention, and hemodialysis.

It is noted that thrombosis includes vessel occlusion (e.g. after abypass) and reocclusion (e.g., during or after percutaneous transluminalcoronary angioplasty). The thromboembolic disorders may result fromconditions including but not limited to atherosclerosis, surgery orsurgical complications, prolonged immobilization, arterial fibrillation,congenital thrombophilia, cancer, diabetes, effects of medications orhormones, and complications of pregnancy. The anticoagulant effect ofcompounds of the present invention is believed to be due to inhibitionof serine proteases involved in the coagulation cascade and/or contactactivation system, more specifically, inhibition of the coagulationfactors: factor XIa, factor VIIa, factor IXa, factor Xa, plasmakallikrein or thrombin.

The term “thrombosis”, as used herein, refers to formation or presenceof a thrombus (pl. thrombi); clotting within a blood vessel which maycause ischemia or infarction of tissues supplied by the vessel. The term“embolism”, as used herein, refers to sudden blocking of an artery by aclot or foreign material which has been brought to its site of lodgmentby the blood current. The term “thromboembolism”, as used herein, refersto obstruction of a blood vessel with thrombotic material carried by theblood stream from the site of origin to plug another vessel. The term“stroke”, as used herein, refers to embolic stroke or atherothromboticstroke arising from occlusive thrombosis in the carotid communis,carotid interna, or intracerebral arteries.

The compounds of this invention also are inhibitors of plasma kallikreinand are useful as anti-inflammatory agents for the treatment orprevention of diseases associated with an activation of the contactactivation system (i.e., plasma kallikrein associated disorders). Ingeneral, a contact activation system disorder is a disease caused byactivation of blood on artificial surfaces, including prosthetic valvesor other implants, indwelling catheters, stents, cardiopulmonary bypass,hemodialysis, microorganism (e.g., bacteria, virus), or other proceduresin which blood is exposed to an artificial surface that promotes contactactivation, blood clots (i.e., diseases involving fibrin formation,platelet activation, and/or platelet aggregation). Contact activationcan also occur on cell surfaces, cellular receptors or extracellularmatrices, Diseases of the contact activation system also includesystemic inflammatory response syndrome, sepsis, acute respiratorydistress syndrome, hereditary angioedema or other inherited or acquireddeficiencies of contact activation components or their inhibitors(plasma kallikrein, factor XIIa, high molecular weight kininogen,C1-esterase inhibitor). It may also include acute and chronicinflammations of joints, vessels, or other mammalian organs.

The effectiveness of compounds of the present invention as inhibitors ofthe coagulation factors XIa, VIIa, IXa, Xa, plasma kallikrein orthrombin, can be determined using a relevant purified serine protease,respectively, and an appropriate synthetic substrate. The rate ofhydrolysis of the chromogenic or fluorogenic substrate by the relevantserine protease was measured both in the absence and presence ofcompounds of the present invention. Hydrolysis of the substrate resultedin the release of pNA (para nitroaniline), which was monitoredspectrophotometrically by measuring the increase in absorbance at 405nm, or the release of AMC (amino methylcoumarin), which was monitoredspectrofluorometrically by measuring the increase in emission at 460 nmwith excitation at 380 nm. A decrease in the rate of absorbance orfluorescence change in the presence of inhibitor is indicative of enzymeinhibition. Such methods are known to one skilled in the art. Theresults of this assay are expressed as the inhibitory constant, K_(i).

Factor XIa determinations were made in 50 mM HEPES buffer at pH 7.4containing 145 mM NaCl, 5 mM KCl, and 0.1% PEG 8000 (polyethyleneglycol; J T Baker or Fisher Scientific). Determinations were made usingpurified human Factor XIa at a final concentration of 75-200 pM(Haematologic Technologies) and the synthetic substrate S-2366(pyroGlu-Pro-Arg-pNA; Chromogenix) at a concentration of 0.0002-0.00025M. In general, preferred compounds of the present invention, such as theparticular compounds disclosed in the above examples, have beenidentified to be active and exhibit K_(i)'s of equal to or less than 15μM in the Factor XIa assay, thereby demonstrating the utility of thecompounds of the present invention as especially effective inhibitors ofcoagulation Factor XIa. More preferred compounds have K_(i)'s of equalto or less than 5 μM, preferably equal to or less than 1 μM, morepreferably equal to or less than 0.5 μM.

Factor VIIa determinations were made in 0.005 M calcium chloride,

-   0.15 M sodium chloride, 0.05 M HEPES buffer containing 0.5% PEG 8000    at a pH of 7.4. Determinations were made using purified human Factor    VIIa (Haematologic Technologies) or recombinant human Factor VIIa    (Novo Nordisk) at a final assay concentration of 2-5 nM, recombinant    soluble tissue factor at a concentration of 18-35 nM and the    synthetic substrate H-D-Ile-Pro-Arg-pNA (S-2288; Chromogenix or    BMPM-2; AnaSpec) at a concentration of 0.001 M. In general,    compounds tested in the Factor VIIa assay are considered to be    active if they exhibit a K_(i) of equal to or less than 15 μM.

Factor IXa determinations were made in 0.005 M calcium chloride, 0.1 Msodium chloride, 0.05 M TRIS base and 0.5% PEG 8000 at a pH of 7.4.Determinations were made using purified human Factor IXa (HaematologicTechnologies) at a final assay concentration of 20-100 nM and thesynthetic substrate PCIXA2100-B (CenterChem) or Pefafluor IXa 3688(H-D-Leu-Ph′Gly-Arg-AMC; CenterChem) at a concentration of 0.0004-0.0005M. In general, compounds tested in the Factor IXa assay are consideredto be active if they exhibit a K_(i) of equal to or less than 15 μM.

Factor Xa determinations were made in 0.1 M sodium phosphate buffer at apH of 7.4 containing 0.2 M sodium chloride and 0.5% PEG 8000.Determinations were made using purified human Factor Xa (HaematologicTechnologies) at a final assay concentration of 150-1000 μM and thesynthetic substrate S-2222 (Bz-Ile-Glu (gamma-OMe, 50%)-Gly-Arg-pNA;Chromogenix) at a concentration of 0.0002-0.0003 M. In general,compounds tested in the Factor Xa assay are considered to be active ifthey exhibit a K_(i) of equal to or less than 15 μM.

Plasma kallikrein determinations were made in 0.1 M sodium phosphatebuffer at a pH of 7.4 containing 0.2 M sodium chloride and 0.5% PEG8000. Determinations were made using purified human kallikrein (EnzymeResearch Laboratories) at a final assay concentration of 200 μM and thesynthetic substrate S-2302 (H-(D)-Pro-Phe-Arg-pNA; Chromogenix) at aconcentration of 0.00008-0.0004 M. The Km value used for calculation ofKi was 0.00005 to 0.00007 M. In general, Compounds tested in the plasmakallikrein assay are considered to be active if they exhibit a K_(i) ofequal to or less than 15 μM.

Thrombin determinations were made in 0.1 M sodium phosphate buffer at apH of 7.4 containing 0.2 M sodium chloride and 0.5% PEG 8000.Determinations were made using purified human alpha thrombin(Haematologic Technologies or Enzyme Research Laboratories) at a finalassay concentration of 200-250 μM and the synthetic substrate S-2366(pyroGlu-Pro-Arg-pNA; Chromogenix) at a concentration of 0.0002 M. Ingeneral, compounds tested in the thrombin assay are considered to beactive if they exhibit a K_(i) of equal to or less than 15 μM.

In general, preferred compounds of the present invention havedemonstrated K_(i) values of equal to or less than 15 μM in at least oneof the above assays, thereby confirming the utility of the compounds ofthe present invention as effective inhibitors of the coagulation cascadeand/or contact activation system, and useful as anticoagulants for theprevention or treatment of thromboembolic disorders in mammals and/or asanti-inflammatory agents for the prevention or treatment of inflammatorydisorders in mammals.

The Michaelis constant, K_(m), for substrate hydrolysis by each proteasewas determined at 25° C. using the method of Lineweaver and Burk. Valuesof K_(i) were determined by allowing the protease to react with thesubstrate in the presence of the inhibitor. Reactions were allowed to gofor periods of 20-180 minutes (depending on the protease) and thevelocities (rate of absorbance or fluorescence change versus time) weremeasured. The following relationships were used to calculate K_(i)values:(v _(O) −v _(S))/v _(S) =I/(K _(i)(1+S/K _(m))) for a competitiveinhibitor with one binding site; orv _(S) /v _(O) =A+((B−A)/1+((IC₅₀/(I)^(n)))) andK _(i)=IC₅₀/(1+S/K _(m)) for a competitive inhibitor

where:

-   -   v_(O) is the velocity of the control in the absence of        inhibitor;    -   v_(S) is the velocity in the presence of inhibitor;    -   I is the concentration of inhibitor;    -   A is the minimum activity remaining (usually locked at zero);    -   B is the maximum activity remaining (usually locked at 1.0);    -   n is the Hill coefficient, a measure of the number and        cooperativity of potential inhibitor binding sites;    -   IC₅₀ is the concentration of inhibitor that produces 50%        inhibition under the assay conditions;    -   K_(i) is the dissociation constant of the enzyme: inhibitor        complex;    -   S is the concentration of substrate; and    -   K_(m) is the Michaelis constant for the substrate.

The effectiveness of compounds of the present invention asantithrombotic agents can be determined using relevant in vivothrombosis models, including In Vivo Electrically-induced Carotid ArteryThrombosis Models and In Vivo Rabbit Arterio-venous Shunt ThrombosisModels.

In Vivo Electrically-Induced Carotid Artery Thrombosis (ECAT) Model:

The rabbit ECAT model, described by Wong et al. (J Pharmacol Exp Ther2000, 295, 212-218), can be used in this study. Male New Zealand Whiterabbits are anesthetized with ketamine (50 mg/kg+50 mg/kg/h IM) andxylazine (10 mg/kg+10 mg/kg/h IM). These anesthetics are supplemented asneeded. An electromagnetic flow probe is placed on a segment of anisolated carotid artery to monitor blood flow. Test agents or vehiclewill be given (i.v., i.p., s.c., or orally) prior to the initiation ofthrombosis. Thrombus formation is induced by electrical stimulation ofthe carotid artery for 3 min at 4 mA using an external stainless-steelbipolar electrode. Carotid blood flow is measured continuously over a90-min period to monitor thrombus-induced occlusion. Total carotid bloodflow over 90 min is calculated by trapezoidal rule. Average carotid flowover 90 min is then determined by converting total carotid blood flowover 90 min to percent of total control carotid blood flow, which wouldresult if control blood flow had been maintained continuously for 90min. The ED₅₀ (dose that increased average carotid blood flow over 90min to 50% of the control) of compounds are estimated by a nonlinearleast square regression program using the Hill sigmoid E_(max) equation(DeltaGraph; SPSS Inc., Chicago, Ill.).

In Vivo Rabbit Arterio-Venous (AV) Shunt Thrombosis Model

The rabbit AV shunt model, described by Wong et al. (Wong, P. C. et al.J Pharmacol Exp Ther 2000, 292, 351-357), can be used in this study.Male New Zealand White rabbits are anesthetized with ketamine (50mg/kg+50 mg/kg/h IM) and xylazine (10 mg/kg+10 mg/kg/h IM). Theseanesthetics are supplemented as needed. The femoral artery, jugular veinand femoral vein are isolated and catheterized. A saline-filled AV shuntdevice is connected between the femoral arterial and the femoral venouscannulae. The AV shunt device consists of an outer piece of tygon tubing(length=8 cm; internal diameter=7.9 mm) and an inner piece of tubing(length=2.5 cm; internal diameter=4.8 mm). The AV shunt also contains an8-cm-long 2-0 silk thread (Ethicon, Somerville, N.J.). Blood flows fromthe femoral artery via the AV-shunt into the femoral vein. The exposureof flowing blood to a silk thread induces the formation of a significantthrombus. Forty minutes later, the shunt is disconnected and the silkthread covered with thrombus is weighed. Test agents or vehicle will begiven (i.v., i.p., s.c., or orally) prior to the opening of the AVshunt. The percentage inhibition of thrombus formation is determined foreach treatment group. The ID₅₀ values (dose which produces 50%inhibition of thrombus formation) are estimated by a nonlinear leastsquare regression program using the Hill sigmoid E_(max) equation(DeltaGraph; SPSS Inc., Chicago, Ill.).

The anti-inflammatory effect of these compounds can be demonstrated inan Evans Blue dye extravasation assay using C1-esterase inhibitordeficient mice. In this model, mice are dosed with a compound of thepresent invention, Evans Blue is injected via the tail vein, andextravasation of the blue dye is determined by spectrophotometric meansfrom tissue extracts.

The ability of the compounds of the current invention to reduce orprevent the systemic inflammatory response syndrome, for example, asobserved during on-pump cardiovascular procedures, can be tested in invitro perfusion systems, or by on-pump surgical procedures in largermammals, including dogs and baboons. Read-outs to assess the benefit ofthe compounds of the present invention include for example reducedplatelet loss, reduced platelet/white blood cell complexes, reducedneutrophil elastase levels in plasma, reduced activation of complementfactors, and reduced activation and/or consumption of contact activationproteins (plasma kallikrein, factor XII, factor XI, high molecularweight kininogen, C1-esterase inhibitors).

The utility of the compounds of the current invention to reduce orprevent the morbidity and/or mortality of sepsis can be assessed byinjecting a mammalian host with bacteria or viruses or extracts there ofand compounds of the present invention. Typical read-outs of theefficacy include changes in the LD50 and blood pressure preservation.

The compounds of the present invention may also be useful as inhibitorsof additional serine proteases, notably human thrombin, human plasmakallikrein and human plasmin. Because of their inhibitory action, thesecompounds are indicated for use in the prevention or treatment ofphysiological reactions, including blood coagulation, fibrinolysis,blood pressure regulation and inflammation, and wound healing catalyzedby the aforesaid class of enzymes. Specifically, the compounds haveutility as drugs for the treatment of diseases arising from elevatedthrombin activity of the aforementioned serine proteases, such asmyocardial infarction, and as reagents used as anticoagulants in theprocessing of blood to plasma for diagnostic and other commercialpurposes.

The compounds of the present invention can be administered alone or incombination with one or more additional therapeutic agents. Theseinclude other anti-coagulant or coagulation inhibitory agents,anti-platelet or platelet inhibitory agents, anti-inflammatory agents,thrombin inhibitors, or thrombolytic or fibrinolytic agents.

The compounds are administered to a mammal in a therapeuticallyeffective amount. By “therapeutically effective amount” it is meant anamount of a compound of the present invention that, when administeredalone or in combination with an additional therapeutic agent to amammal, is effective to treat (i.e. prevent, inhibit or ameliorate) thethromboembolic and/or inflammatory disease condition or treat theprogression of the disease in a host.

By “administered in combination” or “combination therapy” it is meantthat the compound of the present invention and one or more additionaltherapeutic agents are administered concurrently to the mammal beingtreated. When administered in combination each component may beadministered at the same time or sequentially in any order at differentpoints in time. Thus, each component may be administered separately butsufficiently closely in time so as to provide the desired therapeuticeffect.

Compounds which can be administered in combination with the compounds ofthe present invention include, but are not limited to, anticoagulants,anti-thrombin agents, anti-platelet agents, fibrinolytics, hypolipidemicagents, antihypertensive agents, and anti-ischemic agents.

Other anticoagulant agents (or coagulation inhibitory agents) that maybe used in combination with the compounds of this invention includewarfarin, heparin (either unfractionated heparin or any commerciallyavailable low molecular weight heparin, for example LOVENOX™), syntheticpentasaccharide, direct acting thrombin inhibitors including hirudin andargatroban, as well as other factor VIIa inhibitors, factor IXainhibitors, factor Xa inhibitors (e.g., Arixtra™, apixaban, rivaroxaban,LY-517717, DU-176b, DX-9065a, and those disclosed in WO 98/57951, WO03/026652, WO 01/047919, and WO 00/076970), factor XIa inhibitors, andinhibitors of activated TAFI and PAI-1 known in the art.

The term anti-platelet agents (or platelet inhibitory agents), as usedherein, denotes agents that inhibit platelet function, for example, byinhibiting the aggregation, adhesion or granule-content secretion ofplatelets. Such agents include, but are not limited to, the variousknown non-steroidal anti-inflammatory drugs (NSAIDS) such asacetaminophen, aspirin, codeine, diclofenac, droxicam, fentaynl,ibuprofen, indomethacin, ketorolac, mefenamate, morphine, naproxen,phenacetin, piroxicam, sufentanyl, sulfinpyrazone, sulindac, andpharmaceutically acceptable salts or prodrugs thereof. Of the NSAIDS,aspirin (acetylsalicylic acid or ASA), and piroxicam are preferred.Other suitable platelet inhibitory agents include glycoprotein IIb/IIIaantagonists (e.g., tirofiban, eptifibatide, abciximab, and integrelin),thromboxane-A2-receptor antagonists (e.g., ifetroban),thromboxane-A-synthetase inhibitors, phosphodiesterase-III (PDE-III)inhibitors (e.g., dipyridamole, cilostazol), and PDE-V inhibitors (suchas sildenafil), protease-activated receptor 1 (PAR1) antagonists (e.g.,SCH-530348, SCH-203099, SCH-529153 and SCH-205831), and pharmaceuticallyacceptable salts or prodrugs thereof.

Other examples of suitable anti-platelet agents for use in combinationwith the compounds of the present invention, with or without aspirin,ADP (adenosine diphosphate) receptor antagonists, preferably antagonistsof the purinergic receptors P₂Y₁ and P₂Y₁₂, with P₂Y₁₂ being even morepreferred. Preferred P₂Y₁₂ receptor antagonists include clopidogrel,ticlopidine, prasugrel, and AZD-6140, and pharmaceutically acceptablesalts or prodrugs thereof. Ticlopidine and clopidogrel are alsopreferred compounds since they are known to be more gentle than aspirinon the gastro-intestinal tract in use. Clopidogrel is an even morepreferred agent.

The term thrombin inhibitors (or anti-thrombin agents), as used herein,denotes inhibitors of the serine protease thrombin. By inhibitingthrombin, various thrombin-mediated processes, such as thrombin-mediatedplatelet activation (that is, for example, the aggregation of platelets,and/or the secretion of platelet granule contents including serotonin)and/or fibrin formation are disrupted. A number of thrombin inhibitorsare known to one of skill in the art and these inhibitors arecontemplated to be used in combination with the present compounds. Suchinhibitors include, but are not limited to, boroarginine derivatives,boropeptides, heparins, hirudin, argatroban, dabigatran, AZD-0837, andthose disclosed in WO 98/37075 and WO 02/044145, and pharmaceuticallyacceptable salts and prodrugs thereof. Boroarginine derivatives andboropeptides include N-acetyl and peptide derivatives of boronic acid,such as C-terminal a-aminoboronic acid derivatives of lysine, ornithine,arginine, homoarginine and corresponding isothiouronium analogs thereof.The term hirudin, as used herein, includes suitable derivatives oranalogs of hirudin, referred to herein as hirulogs, such asdisulfatohirudin.

The term thrombolytic (or fibrinolytic) agents (or thrombolytics orfibrinolytics), as used herein, denotes agents that lyse blood clots(thrombi). Such agents include tissue plasminogen activator (TPA,natural or recombinant) and modified forms thereof, anistreplase,urokinase, streptokinase, tenecteplase (TNK), lanoteplase (nPA), factorVIIa inhibitors, thrombin inhibitors, inhibitors of factors IXa, Xa, andXIa, PAI-I inhibitors (i.e., inactivators of tissue plasminogenactivator inhibitors), inhibitors of activated TAFI, alpha-2-antiplasmininhibitors, and anisoylated plasminogen streptokinase activator complex,including pharmaceutically acceptable salts or prodrugs thereof. Theterm anistreplase, as used herein, refers to anisoylated plasminogenstreptokinase activator complex, as described, for example, in EuropeanPatent Application No. 028,489, the disclosure of which is herebyincorporated herein by reference herein. The term urokinase, as usedherein, is intended to denote both dual and single chain urokinase, thelatter also being referred to herein as prourokinase.

Examples of suitable anti-arrhythmic agents for use in combination withthe present compounds include: Class I agents (such as propafenone);Class II agents (such as carvadiol and propranolol); Class III agents(such as sotalol, dofetilide, amiodarone, azimilide and ibutilide);Class IV agents (such as ditiazem and verapamil); K⁺ channel openerssuch as I_(Ach) inhibitors, and I_(Kur) inhibitors (e.g., compounds suchas those disclosed in WO01/40231).

Examples of suitable antihypertensive agents for use in combination withthe compounds of the present invention include alpha adrenergicblockers; beta adrenergic blockers; calcium channel blockers (e.g.,diltiazem, verapamil, nifedipine, amlodipine and mybefradil); diruetics(e.g., chlorothiazide, hydrochlorothiazide, flumethiazide,hydroflumethiazide, bendroflumethiazide, methylchlorothiazide,trichloromethiazide, polythiazide, benzthiazide, ethacrynic acidtricrynafen, chlorthalidone, furosemide, musolimine, bumetanide,triamtrenene, amiloride, spironolactone); renin inhibitors;angiotensin-converting enzyme (ACE) inhibitors (e.g., captopril,lisinopril, fosinopril, enalapril, ceranopril, cilazopril, delapril,pentopril, quinapril, ramipril, lisinopril), angiotensin AT-1 receptorantagonists (e.g., irbesartan, losartan, valsartan); ET-A receptorantagonists (e.g., sitaxsentan, atrsentan and compounds disclosed inU.S. Pat. Nos. 5,612,359 and 6,043,265); Dual ET-A/AT-1 antagonist(e.g., compounds disclosed in WO 00/01389); neutral endopeptidase (NEP)inhibitors; vasopepsidase inhibitors (dual ACE/NEP inhibitors, e.g.,omapatrilat gemopatrilat, nitrates) and β-blockers (for examplepropanolol, nadolo, or carvedilol).

Examples of suitable calcium channel blockers (L-type or T-type) for usein combination with the compounds of the present invention includediltiazem, verapamil, nifedipine, amlodipine and mybefradil.

Examples of suitable cardiac glycosides for use in combination with thecompounds of the present invention include digitalis and ouabain.

Examples of suitable diruetics for use in combination with the compoundsof the present invention include: chlorothiazide, hydrochlorothiazide,flumethiazide, hydroflumethiazide, bendroflumethiazide,methylchlorothiazide, trichloromethiazide, polythiazide, benzthiazide,ethacrynic acid tricrynafen, chlorthalidone, furosemide, musolimine,bumetanide, triamtrenene, amiloride, and spironolactone.

Examples of suitable mineralocorticoid receptor antagonists for use incombination with the compounds of the present invention includesprionolactone and eplirinone.

Examples of suitable anti-diabetic agents for use in combination withthe compounds of the present invention include: biguanides (e.g.,metformin); glucosidase inhibitors (e.g., acarbose); insulins (includinginsulin secretagogues or insulin sensitizers); meglitinides (e.g.,repaglinide); sulfonylureas (e.g., glimepiride, glyburide andglipizide); biguanide/glyburide combinations (e.g., glucovance),thiozolidinediones (e.g., troglitazone, rosiglitazone and pioglitazone),PPAR-alpha agonists, PPAR-gamma agonists, PPAR alpha/gamma dualagonists, SGLT2 inhibitors, inhibitors of fatty acid binding protein(aP2) such as those disclosed in WO00/59506, glucagon-like peptide-1(GLP-1), and dipeptidyl peptidase IV (DPP4) inhibitors.

Examples of suitable anti-depressant agents for use in combination withthe compounds of the present invention include nefazodone andsertraline.

Examples of suitable anti-inflammatory agents for use in combinationwith the compounds of the present invention include: prednisone;dexamethasone; enbrel; protein tyrosine kinase (PTK) inhibitors;cyclooxygenase inhibitors (including NSAIDs, and COX-1 and/or COX-2inhibitors); aspirin; indomethacin; ibuprofen; prioxicam; naproxen;celecoxib; and/or rofecoxib.

Examples of suitable anti-osteoporosis agents for use in combinationwith the compounds of the present invention include alendronate andraloxifene.

Examples of suitable hormone replacement therapies for use incombination with the compounds of the present invention include estrogen(e.g., conjugated estrogens) and estradiol.

Examples of suitable anti-obesity agents for use in combination with thecompounds of the present invention include orlistat, aP2 inhibitors(such as those disclosed in WO00/59506), and cannabinoid receptor CB 1antagonists (e.g., rimonabant, AVE-1625, SR-147778, and CP-945598).

Examples of suitable anti-anxiety agents for use in combination with thecompounds of the present invention include diazepam, lorazepam,buspirone, and hydroxyzine pamoate.

Examples of suitable anti-proliferative agents for use in combinationwith the compounds of the present invention include cyclosporin A,paclitaxel, adriamycin; epithilones, cisplatin, and carboplatin.

Examples of suitable holesterol/lipid lowering agents and lipid profiletherapies for use in combination with the compounds of the presentinvention include HMG-CoA reductase inhibitors (e.g, pravastatin,lovastatin, simvastatin, fluvastatin, atorvsatatin, rosuvastatin, andother statins), sequestrants (e.g., cholestyramine and colestipol),nicotonic acid, fenofibric acid derivatives (e.g., gemfibrozil,clofibrat, fenofibrate and benzafibrate), probucol, choesterolabsorption inhibitors, and cholesterol ester transfer protein inhibitors(e.g., CP-529414).

Examples of suitable anti-ulcer and gastroesophageal reflux diseaseagents for use in combination with the compounds of the presentinvention include famotidine, ranitidine, and omeprazole.

Administration of the compounds of the present invention (i.e., a firsttherapeutic agent) in combination with at least one additionaltherapeutic agent (i.e., a second therapeutic agent), preferably affordsan efficacy advantage over the compounds and agents alone, preferablywhile permitting the use of lower doses of each. A lower dosageminimizes the potential of side effects, thereby providing an increasedmargin of safety. It is preferred that at least one of the therapeuticagents is administered in a sub-therapeutic dose. It is even morepreferred that all of the therapeutic agents be administered insub-therapeutic doses. Sub-therapeutic is intended to mean an amount ofa therapeutic agent that by itself does not give the desired therapeuticeffect for the condition or disease being treated. Synergisticcombination is intended to mean that the observed effect of thecombination is greater than the sum of the individual agentsadministered alone.

The compounds of the present invention are also useful as standard orreference compounds, for example as a quality standard or control, intests or assays involving the inhibition of thrombin, Factor VIIa, IXa,Xa, XIa, and/or plasma kallikrein. Such compounds may be provided in acommercial kit, for example, for use in pharmaceutical researchinvolving thrombin, Factor VIIa, IXa, Xa, XIa, and/or plasma kallikrein.XIa. For example, a compound of the present invention could be used as areference in an assay to compare its known activity to a compound withan unknown activity. This would ensure the experimenter that the assaywas being performed properly and provide a basis for comparison,especially if the test compound was a derivative of the referencecompound. When developing new assays or protocols, compounds accordingto the present invention could be used to test their effectiveness.

The compounds of the present invention may also be used in diagnosticassays involving thrombin, Factor VIIa, IXa, Xa, XIa, and/or plasmakallikrein. For example, the presence of thrombin, Factor VIIa, IXa, XaXIa, and/or plasma kallikrein in an unknown sample could be determinedby addition of the relevant chromogenic substrate, for example S2366 forFactor XIa, to a series of solutions containing test sample andoptionally one of the compounds of the present invention. If productionof pNA is observed in the solutions containing test sample, but not inthe presence of a compound of the present invention, then one wouldconclude Factor XIa was present.

Extremely potent and selective compounds of the present invention, thosehaving K_(i) values less than or equal to 0.001 μM against the targetprotease and greater than or equal to 0.1 μM against the otherproteases, may also be used in diagnostic assays involving thequantitation of thrombin, Factor VIIa, IXa, Xa, XIa, and/or plasmakallikrein in serum samples. For example, the amount of Factor XIa inserum samples could be determined by careful titration of proteaseactivity in the presence of the relevant chromogenic substrate, S2366,with a potent and selective Factor XIa inhibitor of the presentinvention.

The present invention also encompasses an article of manufacture. Asused herein, article of manufacture is intended to include, but not belimited to, kits and packages. The article of manufacture of the presentinvention, comprises: (a) a first container; (b) a pharmaceuticalcomposition located within the first container, wherein the composition,comprises: a first therapeutic agent, comprising: a compound of thepresent invention or a pharmaceutically acceptable salt form thereof,and, (c) a package insert stating that the pharmaceutical compositioncan be used for the treatment of a thromboembolic and/or inflammatorydisorder (as defined previously). In another embodiment, the packageinsert states that the pharmaceutical composition can be used incombination (as defined previously) with a second therapeutic agent totreat a thromboembolic and/or inflammatory disorder. The article ofmanufacture can further comprise: (d) a second container, whereincomponents (a) and (b) are located within the second container andcomponent (c) is located within or outside of the second container.Located within the first and second containers means that the respectivecontainer holds the item within its boundaries.

The first container is a receptacle used to hold a pharmaceuticalcomposition. This container can be for manufacturing, storing, shipping,and/or individual/bulk selling. First container is intended to cover abottle, jar, vial, flask, syringe, tube (e.g., for a cream preparation),or any other container used to manufacture, hold, store, or distribute apharmaceutical product.

The second container is one used to hold the first container and,optionally, the package insert. Examples of the second containerinclude, but are not limited to, boxes (e.g., cardboard or plastic),crates, cartons, bags (e.g., paper or plastic bags), pouches, and sacks.The package insert can be physically attached to the outside of thefirst container via tape, glue, staple, or another method of attachment,or it can rest inside the second container without any physical means ofattachment to the first container. Alternatively, the package insert islocated on the outside of the second container. When located on theoutside of the second container, it is preferable that the packageinsert is physically attached via tape, glue, staple, or another methodof attachment. Alternatively, it can be adjacent to or touching theoutside of the second container without being physically attached.

The package insert is a label, tag, marker, etc. that recitesinformation relating to the pharmaceutical composition located withinthe first container. The information recited will usually be determinedby the regulatory agency governing the area in which the article ofmanufacture is to be sold (e.g., the United States Food and DrugAdministration). Preferably, the package insert specifically recites theindications for which the pharmaceutical composition has been approved.The package insert may be made of any material on which a person canread information contained therein or thereon. Preferably, the packageinsert is a printable material (e.g., paper, plastic, cardboard, foil,adhesive-backed paper or plastic, etc.) on which the desired informationhas been formed (e.g., printed or applied).

Dosage and Formulation

The compounds of this invention can be administered in such oral dosageforms as tablets, capsules (each of which includes sustained release ortimed release formulations), pills, powders, granules, elixirs,tinctures, suspensions, syrups, and emulsions. They may also beadministered in intravenous (bolus or infusion), intraperitoneal,subcutaneous, or intramuscular form, all using dosage forms well knownto those of ordinary skill in the pharmaceutical arts. They can beadministered alone, but generally will be administered with apharmaceutical carrier selected on the basis of the chosen route ofadministration and standard pharmaceutical practice.

The dosage regimen for the compounds of the present invention will, ofcourse, vary depending upon known factors, such as the pharmacodynamiccharacteristics of the particular agent and its mode and route ofadministration; the species, age, sex, health, medical condition, andweight of the recipient; the nature and extent of the symptoms; the kindof concurrent treatment; the frequency of treatment; the route ofadministration, the renal and hepatic function of the patient, and theeffect desired. A physician or veterinarian can determine and prescribethe effective amount of the drug required to prevent, counter, or arrestthe progress of the thromboembolic disorder.

By way of general guidance, the daily oral dosage of each activeingredient, when used for the indicated effects, will range betweenabout 0.001 to 1000 mg/kg of body weight, preferably between about 0.01to 100 mg/kg of body weight per day, and most preferably between about0.1 to 20 mg/kg/day. Intravenously, the most preferred doses will rangefrom about 0.001 to about 10 mg/kg/minute during a constant rateinfusion. Compounds of this invention may be administered in a singledaily dose, or the total daily dosage may be administered in divideddoses of two, three, or four times daily.

Compounds of this invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal routes,using transdermal skin patches. When administered in the form of atransdermal delivery system, the dosage administration will, of course,be continuous rather than intermittent throughout the dosage regimen.

The compounds are typically administered in admixture with suitablepharmaceutical diluents, excipients, or carriers (collectively referredto herein as pharmaceutical carriers) suitably selected with respect tothe intended form of administration, that is, oral tablets, capsules,elixirs, syrups and the like, and consistent with conventionalpharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl callulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water, and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents, and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth, or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes, and the like. Lubricants used in thesedosage forms include sodium oleate, sodium stearate, magnesium stearate,sodium benzoate, sodium acetate, sodium chloride, and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum, and the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine, or phosphatidylcholines.

Compounds of the present invention may also be coupled with solublepolymers as targetable drug carriers. Such polymers can includepolyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamidephenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacylates, andcrosslinked or amphipathic block copolymers of hydrogels.

Dosage forms (pharmaceutical compositions) suitable for administrationmay contain from about 1 milligram to about 1000 milligrams of activeingredient per dosage unit. In these pharmaceutical compositions theactive ingredient will ordinarily be present in an amount of about0.1-95% by weight based on the total weight of the composition.

Gelatin capsules may contain the active ingredient and powderedcarriers, such as lactose, starch, cellulose derivatives, magnesiumstearate, stearic acid, and the like. Similar diluents can be used tomake compressed tablets. Both tablets and capsules can be manufacturedas sustained release products to provide for continuous release ofmedication over a period of hours. Compressed tablets can be sugarcoated or film coated to mask any unpleasant taste and protect thetablet from the atmosphere, or enteric coated for selectivedisintegration in the gastrointestinal tract.

Liquid dosage forms for oral administration can contain coloring andflavoring to increase patient acceptance.

In general, water, a suitable oil, saline, aqueous dextrose (glucose),and related sugar solutions and glycols such as propylene glycol orpolyethylene glycols are suitable carriers for parenteral solutions.Solutions for parenteral administration preferably contain a watersoluble salt of the active ingredient, suitable stabilizing agents, andif necessary, buffer substances. Antioxidizing agents such as sodiumbisulfite, sodium sulfite, or ascorbic acid, either alone or combined,are suitable stabilizing agents. Also used are citric acid and its saltsand sodium EDTA. In addition, parenteral solutions can containpreservatives, such as benzalkonium chloride, methyl- or propyl-paraben,and chlorobutanol.

Suitable pharmaceutical carriers are described in Remington'sPharmaceutical Sciences, Mack Publishing Company, a standard referencetext in this field.

Where the compounds of this invention are combined with otheranticoagulant agents, for example, a daily dosage may be about 0.1 to100 milligrams of the compound of the present invention and about 0.1 to7.5 milligrams of the second anticoagulant, per kilogram of patient bodyweight. For a tablet dosage form, the compounds of this inventiongenerally may be present in an amount of about 5 to 100 milligrams perdosage unit, and the second anti-coagulant in an amount of about 1 to 50milligrams per dosage unit.

Where the compounds of the present invention are administered incombination with an anti-platelet agent, by way of general guidance,typically a daily dosage may be about 0.01 to 25 milligrams of thecompound of the present invention and about 50 to 150 milligrams of theanti-platelet agent, preferably about 0.1 to 1 milligrams of thecompound of the present invention and about 1 to 3 milligrams ofantiplatelet agents, per kilogram of patient body weight.

Where the compounds of the present invention are administered incombination with thrombolytic agent, typically a daily dosage may beabout 0.1 to 1 milligrams of the compound of the present invention, perkilogram of patient body weight and, in the case of the thrombolyticagents, the usual dosage of the thrombolytic agent when administeredalone may be reduced by about 50-80% when administered with a compoundof the present invention.

Where two or more of the foregoing second therapeutic agents areadministered with the compound of the present invention, generally theamount of each component in a typical daily dosage and typical dosageform may be reduced relative to the usual dosage of the agent whenadministered alone, in view of the additive or synergistic effect of thetherapeutic agents when administered in combination.

Particularly when provided as a single dosage unit, the potential existsfor a chemical interaction between the combined active ingredients. Forthis reason, when the compound of the present invention and a secondtherapeutic agent are combined in a single dosage unit they areformulated such that although the active ingredients are combined in asingle dosage unit, the physical contact between the active ingredientsis minimized (that is, reduced). For example, one active ingredient maybe enteric coated. By enteric coating one of the active ingredients, itis possible not only to minimize the contact between the combined activeingredients, but also, it is possible to control the release of one ofthese components in the gastrointestinal tract such that one of thesecomponents is not released in the stomach but rather is released in theintestines. One of the active ingredients may also be coated with amaterial that affects a sustained-release throughout thegastrointestinal tract and also serves to minimize physical contactbetween the combined active ingredients. Furthermore, thesustained-released component can be additionally enteric coated suchthat the release of this component occurs only in the intestine. Stillanother approach would involve the formulation of a combination productin which the one component is coated with a sustained and/or entericrelease polymer, and the other component is also coated with a polymersuch as a low viscosity grade of hydroxypropyl methylcellulose (HPMC) orother appropriate materials as known in the art, in order to furtherseparate the active components. The polymer coating serves to form anadditional barrier to interaction with the other component.

These as well as other ways of minimizing contact between the componentsof combination products of the present invention, whether administeredin a single dosage form or administered in separate forms but at thesame time by the same manner, will be readily apparent to those skilledin the art, once armed with the present disclosure.

What is claimed is:
 1. A compound of Formula (I):

or a stereoisomer, tautomer, pharmaceutically acceptable salt thereof,wherein: A is substituted with 0-1 R¹ and 0-3 R² and is selected fromthe group: C₃₋₇ cycloalkyl, C₃₋₇ cycloalkenyl, phenyl, naphthyl, or a 5-to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p); L₁ is a bond, —CH₂—, —CH₂CH₂—,—CH(NR⁷R⁸)CH₂—, —CH═CH—, —C≡C—, —OCH₂—, —CR⁵R⁶NH—, —CH₂O—, —SCH₂—,—SO₂CH₂—, —CH₂NR¹⁰—, or —NHNH—; R¹ is, independently at each occurrence,H, —NH₂, —NH(C₁₋₃ alkyl), —(CH₂)_(r)NR⁷R⁸, —(CH₂)_(r)NR⁷C(O)OR⁹,—CH(C₁₋₄ alkyl)NH₂, —CH(C₁₋₄ alkyl)₂NH₂, —N(C₁₋₃ alkyl)₂, —C(═NH)NH₂,—C(O)NH₂, —CH₂NH₂, —CH₂NH(C₁₋₃ alkyl), —CH₂N(C₁₋₃ alkyl)₂, —CH₂CH₂NH₂,—CH₂CH₂NH(C₁₋₃ alkyl), —CH₂CH₂N(C₁₋₃ alkyl)₂, —C(═NR^(8a))NR⁸R⁹,—NR⁸CR⁸(═NR^(8a)), —NR⁷R⁸, —C(O)NR⁷R⁸, —S(O)_(p)NR⁸R⁹, F, Cl, Br, I,OCF₃, CF₃, OR^(a), SR^(a), CN or C₁₋₆ alkyl substituted with 0-1 R^(1a);R^(1a) is —C(═NR^(8a))NR⁸R⁹, —NHC(═NR^(8a))NR⁸R⁹, —NR⁸CH(═NR^(8a)),—ONHC(═NR^(8a))NR⁸R⁹, —NR⁷R⁸, —C(O)NR⁷R⁸, F, OCF₃, CF₃, OR^(a), SR^(a),CN, —NR⁸SO₂NR⁸R⁹, —NR⁸SO₂R^(e), or —(CF₂)_(r)CF₃; R² is, independentlyat each occurrence, ═O, F, Cl, Br, I, OCF₃, CF₃, CHF₂, CN, NO₂,—(CH₂)_(r)OR^(a), —(CH₂)_(r)SR^(a), —(CH₂)_(r)C(O)R^(a),—(CH₂)_(r)C(O)OR^(a), —(CH₂)_(r)OC(O)R^(a), —(CH₂)_(r)NR⁷R⁸,—(CH₂)_(r)C(O)NR⁸R⁹, —(CH₂)_(r)NR⁸C(O)R^(e), —(CH₂)_(r)NR⁸C(O)OR^(c),—NR⁸C(O)NR⁸R^(c), —S(O)_(p)NR⁸R⁹, —NR⁸S(O)₂R^(c), —S(O)R^(c),—S(O)₂R^(o), C₁₋₆ alkyl substituted with 0-2 R^(2a), C₂₋₆ alkenylsubstituted with 0-2 R^(2a), C₂₋₆ alkynyl substituted with 0-2 R^(2a),—(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(2b), or—(CH₂)_(r)-5- to 10-membered heterocycle comprising: carbon atoms and1-4 heteroatoms selected from N, O, and S(O)_(p), wherein saidheterocycle is substituted with 0-3 R^(2b); R^(2a) is, independently ateach occurrence, H, F, Cl, Br, I, ═O, ═NR⁸, CN, OCF₃, CF₃, OR^(a),SR^(a), —NR⁷R⁸, —C(O)NR⁸R⁹, —NR⁸C(O)R^(c), —NR⁸C(O)OR^(c),—NR⁸C(O)NR⁸R^(c), —S(O)_(p)NR⁸R⁹, —NR⁸SO₂R^(c), —S(O)R^(c), or—S(O)₂R^(c); R^(2b) is, independently at each occurrence, H, F, Cl, Br,I, ═O, ═NR⁸, —(CH₂)_(r)CN, —(CH₂)_(r)NO₂, —(CH₂)_(r)OR^(a),—(CH₂)_(r)SR^(a), —(CH₂)_(r)C(O)R^(a), —(CH₂)_(r)C(O)OR^(a),—(CH₂)_(r)OC(O)R^(a), —(CH₂)_(r)NR⁷R⁸, —(CH₂)_(r)C(O)NR⁸R⁹,—(CH₂)_(r)NR⁸C(O)R^(c), —(CH₂)_(r)S(O)_(p)NR⁸R⁹, —(CH₂)_(r)SO₂R^(c),—(CH₂)_(r)NR⁸SO₂NR⁸R⁹, —(CH₂)_(r)NR⁸SO₂R^(c), —(CF₂)_(r)CF₃, C₁₋₆ alkyl,C₂₋₆ alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₁₋₄ haloalkyl, or C₁₋₄haloalkyloxy; alternately, when R¹ and R² are substituted on adjacentring atoms, they can be taken together with the ring atoms to which theyare attached to form a 5- to 7-membered carbocycle or heterocyclecomprising: carbon atoms and 0-4 heteroatoms selected from N, O, andS(O)_(p), wherein said carbocycle or heterocycle is substituted with 0-2R⁹; R³ is phenyl substituted with 0-3 R^(3a) and 0-1 R^(3d), naphthylsubstituted with 0-3 R^(3a) and 0-1 R^(3d), or —(CH₂)_(r)-5- to12-membered heterocycle comprising: carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p), wherein said heterocycle issubstituted with 0-3 R^(3a) and 0-1 R^(3d); R^(3a) is, independently ateach occurrence, ═O, ═NR⁸, F, Cl, Br, I, OCF₃, CF₃, —(CH₂)_(r)CN, NO₂,—(CH₂)_(r)OR^(3b), —(CH₂)_(r)—SR^(3b), —(CH₂)_(r)NR⁷R⁸,—C(═NR^(8a))NR⁸R⁹, —NHC(═NR^(8a))NR⁸R⁹, —C(O)OR^(3b), —C(O)C₁₋₄ alkyl,—SO₂NHR^(3b), —SO₂NHCOR^(3c), —SO₂NHCO₂R^(3c), —CONHSO₂R^(3c),—NR⁸CR⁸(═NR^(8a)), —NHC(O)NR⁸R⁹, —(CH₂)_(r)NR⁸C(O)R^(3b),—(CH₂)_(r)NR⁸CO₂R^(3b), —(CH₂)_(r)S(O)_(p)NR⁸R⁹,—(CH₂)_(r)NR⁸S(O)_(p)R^(3c), —NHSO₂CF₃, —S(O)R^(3c), —S(O)₂R^(3c),—(CH₂)_(r)CO₂R^(3b), —(CH₂)_(r)OC(O)R^(3b), —(CH₂)_(r)C(O)NR⁸R⁹,—(CH₂)_(r)OC(O)NR⁸R⁹, —NHCOCF₃, —NHSO₂R^(3c), —CONHOR^(3b), C₁₋₄haloalkyl, C₁₋₄ haloalkyloxy, C₁₋₆ alkyl substituted by R^(3e), C₂₋₆alkenyl substituted by R^(3e), C₁₋₆ alkynyl substituted by R^(3e), C₃₋₆cycloalkyl substituted by 0-1 R^(3d), —(CH₂)_(r)—C₆₋₁₀ carbocyclesubstituted by 0-3 R^(3d) or —(CH₂)_(r)-5- to 10-membered heterocyclecomprising: carbon atoms and 1-4 heteroatoms selected from N, O, andS(O)_(p), wherein said heterocycle is substituted with 0-3 R^(3d);alternately, when two R^(3a) groups are substituted on adjacent atoms,they can be taken together with the atoms to which they are attached toform a C₃₋₁₀ carbocycle substituted with 0-2 R^(3d), or a 5- to10-membered heterocycle comprising: carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p), wherein said heterocycle issubstituted with 0-2 R^(3d); R^(3b) is, independently at eachoccurrence, H, C₁₋₆ alkyl substituted with 0-2 R^(3e), C₂₋₆ alkenylsubstituted with 0-2 R^(3e), C₂₋₆ alkynyl substituted with 0-2 R^(3e),—(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(3d), or—(CH₂)_(r)-5- to 10-membered heterocycle comprising: carbon atoms and1-4 heteroatoms selected from N, O, and S(O)_(p), wherein saidheterocycle is substituted with 0-3 R^(3d); R^(3c) is, independently ateach occurrence, C₁₋₆ alkyl substituted with 0-2 R^(3d), C₂₋₆ alkenylsubstituted with 0-2 R^(3d), C₂₋₆ alkynyl substituted with 0-2 R^(3d),—(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(3d), or—(CH₂)_(r)-5- to 10-membered heterocycle comprising: carbon atoms and1-4 heteroatoms selected from N, O, and S(O)_(p), wherein saidheterocycle is substituted with 0-3 R^(3d); R^(3d) is, independently ateach occurrence, H, ═O, F, Cl, Br, CN, NO₂, —(CH₂)_(r)NR⁷R⁸,—(CH₂)_(r)OR^(a), —C(O)R^(a), —C(O)OR^(a), —OC(O)R^(a), —NR⁸C(O)R^(c),—C(O)NR⁸R⁹, —S(O)₂NR⁸R⁹, —NR⁷R⁸, —NR⁸S(O)₂NR⁸R⁹, —NR⁸S(O)₂R^(c),—S(O)_(p)R^(c), —(CF₂)_(r)CF₃, C₁₋₆ alkyl substituted with 0-2 R^(e),C₂₋₆ alkenyl substituted with 0-2 R^(e), C₂₋₆ alkynyl substituted with0-2 R^(e), —(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(d), or—(CH₂)_(r)-5- to 10-membered heterocycle comprising: carbon atoms and1-4 heteroatoms selected from N, O, and S(O)_(p), wherein saidheterocycle is substituted with 0-3 R^(d); R^(3e) is, independently ateach occurrence, H, —(CH₂)_(r)OR^(a), F, ═O, CN, NO₂, —(CH₂)_(r)NR⁷R⁸,—C(O)R^(a), —C(O)OR^(a), —OC(O)R^(a), —NR⁸C(O)R^(c), —C(O)NR⁸R⁹,—S(O)₂NR⁸R⁹, —NR⁸S(O)₂NR⁸R⁹, —NR⁸S(O)₂R^(c), —S(O)_(p)R^(c),—(CF₂)_(r)CF₃, —(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(d),or —(CH₂)_(r)-5- to 10-membered heterocycle comprising: carbon atoms and1-4 heteroatoms selected from N, O, and S(O)_(p), wherein saidheterocycle is substituted with 0-3 R^(d); R⁴ is, independently at eachoccurrence, H, F, Cl, Br, I, CF₃, CN, NO₂, —(CH₂)_(r)OR^(a),—(CH₂)_(r)SR^(a), —(CH₂)_(r)C(O)R^(a), —(CH₂)_(r)C(O)OR^(a),—(CH₂)_(r)NR⁷R⁸, —(CH₂)_(r)C(O)NR⁸R⁹, —(CH₂)_(r)NR⁸C(O)R^(c),—(CH₂)_(r)NR⁸C(O)₂R^(b), —(CH₂)_(r)NR⁸C(O)NR⁸R⁹, C₁₋₆ alkyl substitutedwith 0-2 R^(4a), C₂₋₆ alkenyl substituted with 0-2 R^(4a), C₂₋₆ alkynylsubstituted with 0-2 R^(4a), —(CH₂)_(r)—C₃₋₁₀ carbocycle substitutedwith 0-3 R^(4b), or —(CH₂)_(r)-5- to 10-membered heterocycle comprising:carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p),wherein said heterocycle is substituted with 0-3 R^(4b); R^(4a) is,independently at each occurrence, H, F, ═O, C₁₋₄ alkyl, OR^(a), SR^(a),CF₃, CN, NO₂, —C(O)R^(a), —C(O)OR^(a), —NR⁷R⁸, —C(O)NR⁸R⁹,—NR⁷C(O)R^(c), —S(O)_(p)NR⁸R⁹, —NR⁸S(O)_(p)R^(c), —S(O)R^(c), or—S(O)₂R^(c); R^(4b) is, independently at each occurrence, H, ═O, ═NR⁸,OR^(a), SR^(a), F, Cl, Br, I, CN, NO₂, —NR⁷R⁸, —C(O)R^(a), —C(O)OR^(a),—NR⁷C(O)R^(c), —C(O)NR⁸R⁹, —SO₂NR⁸R⁹, —S(O)₂R^(c), C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₁₋₄ haloalkyl, or C₁haloalkyloxy; R⁷ is, independently at each occurrence, H, C₁₋₆ alkyl,—(CH₂)_(n)—C₃₋₁₀ carbocycle, —(CH₂)_(n)-(5- to 10-membered heteroaryl),—C(O)W, —CHO, —C(O)₂R^(c), —S(O)₂R^(c), —CONR⁸R^(c), —OCONHR^(c),—C(O)O—(C₁₋₄ alkyl)OC(O)—(C₁₋₄ alkyl), or —C(O)O—(C₁₋₄alkyl)OC(O)—(C₆₋₁₀ aryl); wherein said alkyl, carbocycle, heteroaryl,and aryl are substituted with 0-2 R^(f); wherein said heteroarylcomprises: carbon atoms and 1-4 heteroatoms selected from N, O, andS(O)_(p); R⁸ is, independently at each occurrence, H, C₁₋₆ alkyl,—(CH₂)_(n)-phenyl, or —(CH₂)_(n)-5-to 10-membered heterocyclecomprising: carbon atoms and 1-4 heteroatoms selected from N, O, andS(O)_(p); wherein said alkyl, phenyl and heterocycle are optionallysubstituted with 0-2 R^(f); alternatively, R⁷ and R⁸, when attached tothe same nitrogen, combine to form a 5- to 10-membered heterocyclecomprising: carbon atoms and 0-3 additional heteroatoms selected from N,O, and S(O)_(p), wherein said heterocycle is substituted with 0-2 R^(f);R⁸a is, independently at each occurrence, R⁷, OH, C₁₋₄ alkoxy, (C₆₋₁₀aryl)-C₁₋₄ alkoxy; wherein said aryl is optionally substituted with 0-2R^(f); R⁹ is, independently at each occurrence, H, C₁₋₆ alkyl, or—(CH₂)_(n)-phenyl; wherein said alkyl and phenyl are optionallysubstituted with 0-2 R^(f); alternatively, R⁸ and R⁹, when attached tothe same nitrogen, combine to form a 5- to 12-membered heterocyclecomprising: carbon atoms and 0-2 additional heteroatoms selected from N,O, and S(O)_(p), wherein said heterocycle is substituted with 0-2 R^(d);R¹⁰ is, independently at each occurrence, H, C₁₋₆ alkyl substituted with0-2 R^(10a), —(CH₂)_(r)-phenyl substituted with 0-3 R^(d), or—(CH₂)_(r)-5- to 10-membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), and substituted with 0-3R^(d); R^(10a) is, independently at each occurrence, H, ═O, C₁₋₄ alkyl,OR^(a), SR^(a), F, CF₃, CN, NO₂, —C(O)R^(a), —C(O)OR^(a), —C(O)NR⁸R⁹,—NR⁸C(O)W, —S(O)_(p)NR⁸R⁹, —NR⁸S(O)_(p)R^(c), or —S(O)_(p)R^(c); R¹¹ isC₁₋₄ haloalkyl, —C(O)NR⁸R⁹, —CH₂C(O)NR⁸R⁹, —CH₂CH₂C(O)NR⁸R⁹, —C(O)R^(a),—CH₂C(O)R^(a), —CH₂CH₂C(O)R^(a), —C(O)OR^(a), —CH₂C(O)OR^(a),—CH₂CH₂C(O)OR^(a), C₁₋₂ alkyl substituted with 1-3 R^(ile), C₂₋₆ alkenylsubstituted with 0-3 R^(11a); C₂₋₆ alkynyl substituted with 0-3 R^(11a),—(CH₂)_(s)—C₃₋₇ cycloalkyl substituted with 0-2 R^(11b),—(CH₂)_(s)-phenyl substituted with 0-3 R^(11b), —(CH₂)_(s)-naphthylsubstituted with 0-3 R^(11b), or —(CH₂)_(s)-5- to 10-memberedheterocycle comprising: carbon atoms and 1-4 heteroatoms selected fromN, O, and S(O)_(p), wherein said heterocycle is substituted with 0-3R^(11b); R^(11a) is, independently at each occurrence, H, ═O, C₁₋₄alkyl, OR^(a), SR^(a), F, CF₃, CN, NO₂, —NR⁷R⁸, —C(O)R^(a), —C(O)OR^(a),—C(O)NR⁸R⁹, —NR⁸C(O)R^(c), —NR⁸C(O)OR^(c), —NR⁸CHO, —S(O)_(p)NR⁸R⁹,—NR⁸S(O)_(p)R^(c), —S(O)_(p)R^(c), C₃₋₆ cycloalkyl, C₁₋₄ haloalkyl, C₁₋₄haloalkyloxy, —(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(d), or—(CH₂)_(r)-5- to 10-membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), and substituted with 0-3R^(d); R^(11b) is, independently at each occurrence, H, ═O, ═NR⁸,OR^(a), SR^(a), F, Cl, Br, CN, NO₂, CF₃, OCF₃, OCHF₂, —NR⁷R⁸,—C(O)R^(a), —C(O)OR^(a), —C(O)NR⁸R⁹, —NR⁸C(O)R^(c), —NR⁸C(O)₂R^(c),—S(O)_(p)NR⁸R⁹, —NR⁸S(O)_(p)R^(c), —S(O)_(p)R^(c), C₁₋₆ alkyl, C₂₋₆alkenyl, C₂₋₆ alkynyl, C₃₋₆ cycloalkyl, C₁ haloalkyl, C₁₋₄ haloalkyloxy,—(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(d), or —(CH₂)_(r)-5-to 10-membered heterocycle comprising carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p), and substituted with 0-3 R^(d);alternately, when two R^(11b) groups are substituents on adjacent atomsthey may be taken together with the atoms to which they are attached toform a 5- to 7-membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p) and substituted with 0-2R^(g); R^(11c) is —(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3R^(d); R^(a) is, independently at each occurrence, H, CF₃, C₁₋₆ alkyl,—(CH₂)_(r)—C₃₋₇cycloalkyl, —(CH₂)_(r)—C₆₋₁₀ aryl, or —(CH₂)_(r)-5- to10-membered heteroaryl comprising carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p); wherein said cycloalkyl, aryl orheteroaryl groups are optionally substituted with 0-2 R^(f); R^(b) is,independently at each occurrence, CF₃, OH, C₁ alkoxy, C₁₋₆ alkyl,—(CH₂)_(r)—C₃₋₁₀ carbocycle substituted with 0-3 R^(d), or —(CH₂)_(r)-5-to 10-membered heterocycle comprising: carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p) and substituted with 0-3 R^(d); R^(c)is, independently at each occurrence, CF₃, C₁₋₆ alkyl substituted with0-2 R^(f), C₃₋₆ cycloalkyl substituted with 0-2 R^(f), C₆₋₁₀ aryl, 5- to10-membered heteroaryl, (C₆₋₁₀ aryl)-C₁₋₄ alkyl, or (5-to 10-memberedheteroaryl)-C₁₋₄ alkyl, wherein said aryl is substituted with 0-3 R^(f)and said heteroaryl comprises: carbon atoms and 1-4 heteroatoms selectedfrom N, O, and S(O)_(p) and substituted with 0-3 R^(f); R^(d) is,independently at each occurrence, H, ═O, ═NR⁸, ORE, F, Cl, Br, I, CN,NO₂, —NR⁷R⁸, —C(O)R^(a), —C(O)OR^(a), —OC(O)R^(a), —NR⁸C(O)R^(c),—C(O)NR⁸R⁹, —SO₂NR⁸R⁹, —NR⁸SO₂NR⁸R⁹, —NR⁸SO₂—C₁₋₄ alkyl, —NR⁸SO₂CF₃,—NR⁸SO₂-phenyl, —S(O)₂CF₃, —S(O)_(p)—C₁₋₄ alkyl, —S(O)_(p)-phenyl,—(CF₂)_(r)CF₃, C₁₋₆ alkyl substituted with 0-2 R^(e), C₂₋₆ alkenylsubstituted with 0-2 R^(e), or C₂₋₆ alkynyl substituted with 0-2 R^(e);R^(e) is, independently at each occurrence, ═O, ORE, F, Cl, Br, I, CN,NO₂, —NR⁷R⁸, —C(O)R^(a), —C(O)OR^(a), —NR⁸C(O)R^(c), —C(O)NR⁸R⁹,—SO₂NR⁸R⁹, —NR⁸SO₂NR⁸R⁹, —NR⁸SO₂—C₁₋₄ alkyl, —NR⁸SO₂CF₃, —NR⁸SO₂-phenyl,—S(O)₂CF₃, —S(O)_(p)—C₁₋₄ alkyl, —S(O)_(p)-phenyl, or —(CF₂)_(r)CF₃;R^(f) is, independently at each occurrence, H, ═O, —(CH₂)_(r)OR^(g), F,Cl, Br, I, CN, NO₂, —NR^(g)R^(g), —C(O)R^(g), —C(O)OR^(g),—NR^(g)C(O)R^(g), —C(O)NR^(g)R^(g), —SO₂NR^(g)R^(g),—NR^(g)SO₂NR^(g)R^(g), —NR^(g)SO₂—C₁₋₄ alkyl, —NR^(g)SO₂CF₃,—NR^(g)SO₂-phenyl, —S(O)₂CF₃, —S(O)_(p)—C₁₋₄ alkyl, —S(O)_(p)-phenyl,—(CH₂)_(n)-phenyl, —(CF₂)_(r)CF₃, C₁₋₆ alkyl, C₂₋₆ alkenyl, C₂₋₆alkynyl, —(CH₂)_(n)-phenyl, or —(CH₂)_(n)-5- to 10-membered heterocyclecomprising carbon atoms and 1-4 heteroatoms selected from N, O, andS(O)_(p); alternately, when two R^(f) groups are substituents onadjacent atoms they may be taken together with the atoms to which theyare attached to form a 5-7-membered heterocycle comprising carbon atomsand 1-4 heteroatoms selected from N, O, and S(O)_(p) and substitutedwith 0-2 R^(g); R^(g) is, independently at each occurrence, H, C₁₋₆alkyl, or —(CH₂)_(n)-phenyl; n, at each occurrence, is selected from 0,1, 2, 3, and 4; p, at each occurrence, is selected from 0, 1, and 2; andr, at each occurrence, is selected from 0, 1, 2, 3, and 4; and s, ateach occurrence, is selected from 1, 2, 3, and 4; provided that: whenR¹¹ is —CH₂CO₂H, L₁ is other than —CH₂O—.
 2. A compound according toclaim 1, wherein the compound is of Formula (I), or a stereoisomer,tautomer, pharmaceutically acceptable salt thereof, wherein: R⁴ is,independently at each occurrence, H, Me, Et, F, Cl, Br, I, CF₃, CN, NO₂,—CH₂OH, —CH₂C(O)OR^(a), OR^(a), SR^(a), —C(O)R^(a), —C(O)OR^(a),—(CH₂)_(r)NH₂, —(CH₂)_(r)C(O)NR⁸R⁹, or phenyl substituted with 0-2R^(4b); R^(4b) is, independently at each occurrence, H, F, Cl, Br, I,OR^(a), SR^(a), CN, NO₂, —NR⁷R⁸, —C(O)R^(a), —C(O)OR^(a), —NR⁷C(O)R^(b),—NR⁷C(O)OR^(c), —C(O)NR⁸R⁹, —SO₂NR⁸R⁹, —S(O)₂R^(c), C₁₋₄ alkyl, C₃₋₆cycloalkyl, C₁₋₄ haloalkyl, or C₁₋₄ haloalkyloxy; and R¹¹ is C₁₋₄haloalkyl, —CH₂C(O)NR⁸R⁹, —CH₂CH₂C(O)NR⁸R⁹, —CH₂C(O)R^(a),—CH₂CH₂C(O)R^(a), —CH₂C(O)OR^(a), —CH₂CH₂C(O)OR^(a), C₁₋₂ alkylsubstituted with 1-2 R^(11c), C₂₋₆ alkenyl substituted with 0-2R^(11a),C₂₋₆ alkynyl substituted with 0-2 R^(11a), —(CH₂)_(r)—C₃₋₁₀ carbocyclesubstituted with 0-3R^(11b), or —(CH₂)_(r)-5- to 10-membered heterocyclecomprising: carbon atoms and 1-4 heteroatoms selected from N, O, andS(O)_(p), wherein said heterocycle is substituted with 0-3 R^(11b).
 3. Acompound according to claim 2, wherein the compound is of Formula (I),or a stereoisomer, tautomer, pharmaceutically acceptable salt thereof,wherein: L₁ is a bond, —CH₂—, —CH₂CH₂—, —CH═CH—, —C≡C—, —OCH₂—, —CH₂NH—,—CH₂O—, —SCH₂—, —SO₂CH₂—, or —NHNH—; R¹ is, independently at eachoccurrence, F, Cl, Br, Me, Et, CF₃, OMe, OH, —NH₂, —C(═NH)NH₂, —C(O)NH₂,—CH₂NH₂, or —SO₂NH₂; R² is, independently at each occurrence, F, Cl, Br,CF₃, NO₂, —(CH₂)_(r)OR^(a), —(CH₂)_(r)SR^(a), —C(O)OR^(a), —C(O)NR⁸R⁹,—NR⁸C(O)R^(c), —NR⁸C(O)OR^(c), —NR⁸C(O)NR⁸R^(c), —S(O)_(p)NR⁸R⁹,—NR⁸SO₂R^(c), —NR⁷R⁸, —S(O)R^(c), —S(O)₂R^(c), C₁₋₆ alkyl substitutedwith 0-1 R^(2a), or a 5-7 membered heterocycle comprising carbon atomsand 1-4 heteroatoms selected from N, O, and S(O)_(p), wherein saidheterocycle is substituted with 0-2 R^(2b); alternately, when R¹ and R²groups are substituents on adjacent atoms they may be taken togetherwith the atoms to which they are attached to form a 5- to 7-memberedcarbocycle or heterocycle comprising carbon atoms and 0-4 heteroatomsselected from N, O, and S(O)_(p) and substituted with 0-2 R^(g); R³ isphenyl substituted with 0-2 R^(3a) and 0-1 R^(3d), naphthyl substitutedwith 0-2 R^(3a) and 0-1 R^(3d), or a 5- to 12-membered heterocyclesubstituted with 0-2 R^(1a) and 0-1 R^(3d), wherein said heterocycle isselected from: thiophene, furan, thiazole, tetrazole, pyridine,pyridone, pyrimidine, pyrrole, pyrazole, indole, 2-oxindole,isoindoline, indazole, 7-azaindole, benzofuran, benzothiophene,benzimidazole, benzisoxazole, benzoxazole, quinazoline, quinoline,isoquinoline, quinoxaline, phthalazine, dihydrophthalazine,dihydroisoquinoline, dihydroquinoline, dihydroquinolone, dihydroindole,dihydrobenzimidazole, dihydrobenzoxazine, dihydroquinazoline,dihydroquinoxaline, benzothiazine, benzoxazine, tetrahydrobenzazepine,dihydroazabenzocycloheptene, and tetrahydroquinoline; R^(1a) is,independently at each occurrence, ═O, F, Cl, Br, Me, CN, OH, OMe,—OC(O)(t-Bu), —CH₂OMe, CF₃, COMe, CO₂H, CO₂Me, —CH₂CO₂H, —(CH₂)₂CO₂H,—CH₂CO₂Me, —CH₂CO₂Et, —CH₂CH₂CO₂Et, —CH₂CN, NH₂, —CH₂NH₂, —CH₂NMe₂,—NHCOMe, —NHCO₂Me, —NHCO₂Et, —NHCH₂CH₂CO₂H, —NHCO₂(i-Pr), —NHCO₂(i-Bu),—NHCO₂(t-Bu), —NHCO₂Bn, —NHCO₂CH₂CH₂OMe, —NHCO₂CH₂CH₂CH₂OMe,—NHCO₂CH₂CO₂H, —NHCO₂CH₂CH₂CO₂H, —NHCO₂CH₂CH₂OH, —NHCO₂CH₂CH₂NH₂,—NHCO₂CH₂-tetrahydrofuran-2-yl, —NHCO₂CH₂CH₂-morpholino, —CH₂NHCO₂Me,—NHC(O)NHMe, —NHC(O)N(Me)₂,4-[(1-carbamoyl-cyclopropanecarbonyl)-amino]-, —NHSO₂Me, —SO₂NH₂,SO₂NHMe, —SO₂NHCH₂CH₂OH, —CONH₂, —CONHMe, —CON(Me)₂, —C(O)NHCH₂CH₂OMe,—CH₂CONH₂, —CO(N-morpholino), —NHCH₂CH₂(N-morpholino), —NR⁷R⁸,—NH(1H-imidazol-2-yl), 1H-tetrazol-5-yl, tetrazol-1-yl, pyrimidin-5-yl,or N-morpholino; R⁴ is, independently at each occurrence, H, F, Cl, Br,Me, Et, Pr, CN, CF₃, —CH₂OH, —(CH₂)₂OH, —(CH₂)₃OH, —CH₂NH₂, —(CH₂)₂NH₂,—(CH₂)₃NH₂, CO₂H, —C(O)NH₂, —C(O)NHMe, —C(O)N(Me)₂, —CH₂CO₂H,—CH₂C(O)NH₂, —CH₂CH₂CO₂H, and R¹¹ is C₁₋₄ haloalkyl, —CH₂C(O)NR⁸R⁹,—CH₂CH₂C(O)NR⁸R⁹, —CH₂C(O)W, —CH₂CH₂C(O)R^(c), —CH₂C(O)OR^(a),—CH₂CH₂C(O)OR^(a), C₁₋₂ alkyl substituted with 1-2 R^(11c),—(CH₂)_(r)—C₃₋₇ cycloalkyl substituted with 0-2 R^(11b),—(CH₂)_(r)-indanyl substituted with 0-2 R^(11b), —(CH₂)_(r)-indenylsubstituted with 0-2 R^(11b), —(CH₂)_(r)-phenyl substituted with 0-2R^(11b), —(CH₂)_(r)-naphthyl substituted with 0-2 R^(11b), or—(CH₂)_(r)-5- to 10-membered heterocycle comprising carbon atoms and 1-4heteroatoms selected from N, O, and S(O)_(p), wherein said heterocycleis substituted with 0-2 R^(11b).
 4. A compound according to claim 1,wherein the compound is of Formula (I), or a stereoisomer, tautomer,pharmaceutically acceptable salt thereof, wherein: A is substituted with0-1 R¹ and 0-3 R² and selected from; C₃₋₇ cycloalkyl, phenyl, naphthyl,pyridyl, 1,2,3,4-tetrahydronaphthyl, pyrrolidinyl, indazolyl, indolyl,imidazolyl, furanyl, thienyl, benzimidazolyl, benzisoxazolyl,benzothiazolyl, benzothiophenyl, 3,4-methylenedioxy-phenyl, oxazolyl,isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, quinolinyl,isoquinolinyl, 1H-4-oxo-isoquinazolinyl, 2H-1-oxo-isquinilinyl,3H-4-oxo-quinazolinyl, 3,4-dihydro-2H-1-oxo-isoquinolinyl,2,3-dihydro-isoindolinyl, 5,6,7,8-tetrahydroquinolinyl,1,2,3,4-tetrahydroquinolinyl, 5,6,7,8-tetrahydroisoquinolinyl,1,2,3,4-tetrahydroisoquinolinyl, quinazolinyl, and phthalazinyl; L₁ is abond, —CH₂—, —CH₂CH₂—, —CH═CH—, —C≡C—, or —CH₂NH—; R¹ is, independentlyat each occurrence, F, Cl, Br, CF₃, NH₂, —CH₂NH₂, —C(═NH)NH₂, —C(O)NH₂,—SO₂NH₂, SW, OR^(a), or C₁₋₆ alkyl substituted with 0-1 R^(1a); R² is,independently at each occurrence, ═O, F, Cl, Br, CF₃, Me, Et, OR^(a),CN, NO₂, NR⁷R⁸, —CH₂OMe, —SW, —CH₂SMe, —C(O)OR^(a), —CH₂NR⁷R⁸, —SO₂NH₂,—SO₂Me, —NHSO₂R^(c), —CH₂NHSO₂R^(c), —C(O)NR⁸R⁹, —NHC(O)R^(c),—CH₂NHC(O)R^(c), —NHC(O)OR^(a), —CH₂NHC(O)OR^(a), —NHC(O)NHR^(e),—CH₂NHC(O)NHR^(c), or a 5-7 membered heterocycle substituted with 0-2R^(2b) and selected from: pyrrolidinyl, 2-oxo-1-pyrrolidinyl,piperidinyl, pyrazolyl, triazolyl, or tetrazolyl; alternately, when R¹and R² groups are substituents on adjacent atoms they may be takentogether with the atoms to which they are attached to form a 5- to6-membered heterocycle comprising carbon atoms and 0-4 heteroatomsselected from N, O, and S(O)_(p); R³ is, independently at eachoccurrence, phenyl substituted with 0-2 R^(3a), naphthyl substitutedwith 0-2 R^(3a), or a 5-to 12-membered heterocycle comprising: carbonatoms and 1-2 heteroatoms selected from N, O, and S(O)_(p), wherein saidheterocycle is substituted with 0-2 R^(3a); R^(3a) is, independently ateach occurrence, ═O, F, Cl, Br, Me, CN, OH, OMe, —OC(O)(t-Bu), —CH₂OMe,CF₃, COMe, CO₂H, CO₂Me, —CH₂CO₂H, —(CH₂)₂CO₂H, —CH₂CO₂Me, —CH₂CO₂Et,—CH₂CH₂CO₂Et, —CH₂CN, NH₂, —CH₂NH₂, —CH₂NMe₂, —NHCOMe, —NHCO₂Me,—NHCO₂Et, —NHCH₂CH₂CO₂H, —NHCO₂(i-Pr), —NHCO₂(i-Bu), —NHCO₂(t-Bu),—NHCO₂Bn, —NHCO₂CH₂CH₂OMe, —NHCO₂CH₂CH₂CH₂OMe, —NHCO₂CH₂CO₂H,—NHCO₂CH₂CH₂CO₂H, —NHCO₂CH₂CH₂OH, —NHCO₂CH₂CH₂NH₂,—NHCO₂CH₂-tetrahydrofuran-2-yl, —NHCO₂CH₂CH₂-morpholino, —CH₂NHCO₂Me,—NHC(O)NHMe, —NHC(O)N(Me)₂,4-[(1-carbamoyl-cyclopropanecarbonyl)-amino]-, —NHSO₂Me, —SO₂NH₂,SO₂NHMe, —SO₂NHCH₂CH₂OH, —CONH₂, —CONHMe, —CON(Me)₂, —C(O)NHCH₂CH₂OMe,—CH₂CONH₂, —CO(N-morpholino), —NHCH₂CH₂(N-morpholino), —NR⁷R⁸,—NH(1H-imidazol-2-yl), 1H-tetrazol-5-yl, tetrazol-1-yl, pyrimidin-5-yl,or N-morpholino, or —(CH₂)_(r)-5- to 6-membered heterocycle comprising:carbon atoms and 1-4 heteroatoms selected from N, O, and S(O)_(p),wherein said heterocycle is substituted with 0-1 R^(3a); alternatively,two of R^(3a) groups located on adjacent atoms, they can be takentogether with the atoms to which they are attached to form a 5- to10-membered heterocycle comprising: carbon atoms and 1-4 heteroatomsselected from N, O, and S(O)_(p), wherein said heterocycle issubstituted with 0-2 R^(3d); R⁴ is, independently at each occurrence, H,F, Cl, Br, Me, Et, Pr, CN, CF₃, —CH₂OH, —(CH₂)₂OH, —(CH₂)₃OH, —CH₂NH₂,—(CH₂)₂NH₂, —(CH₂)₃NH₂, CO₂H, —C(O)NH₂, —C(O)NHMe, —C(O)N(Me)₂,—CH₂CO₂H, —CH₂C(O)NH₂, or —CH₂CH₂CO₂H; R¹¹ is C₁₋₄ haloalkyl,—CH₂C(O)NR⁸R⁹, —CH₂CH₂C(O)NR⁸R⁹, —CH₂C(O)R^(a), —CH₂CH₂C(O)R^(a),—CH₂C(O)OR^(a), —CH₂CH₂C(O)OR^(a), —CH₂OBn, —CH₂SBn, C₁₋₂ alkylsubstituted with 1-2 R^(11c), C₂₋₆ alkenyl substituted with 0-2 R^(11a),C₂₋₆ alkynyl substituted with 0-2 R^(11a), —(CH₂)_(r)—C₃₋₇ cycloalkylsubstituted with 0-2 R^(11b), —(CH₂)_(r)-phenyl substituted with 0-2R^(11b), —(CH₂)_(r)-indanyl substituted with 0-2 R^(11b),—(CH₂)_(r)-indenyl substituted with 0-2 R^(11b), —(CH₂)_(r)-naphthylsubstituted with 0-2 R^(11b), or —(CH₂)_(r)-5- to 10-membered heteroarylsubstituted with 0-2 R^(11b) and selected from thiazolyl, oxazolyl,pyrazolyl, triazolyl, tetrazolyl, thiadiazolyl, isoxazolyl, imidazolyl,pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, indolyl, indazolyl,isoindolyl, indolinyl, isoindolinyl, benzimidazolyl, benzothiazolyl,benzotriazolyl, quinolinyl, isoquinolinyl, tetrahydroquinolinyl,tetrahydroisoquinolinyl, and2,2-dioxo-2,3-dihydro-1H-2λ⁶-benzo[c]thiophenyl; and R^(11b) is,independently at each occurrence, H, ═O, F, Cl, Br, CF₃, OMe, OEt,O(i-Pr), OCF₃, OCHF₂, CN, OPh, OBn, NO₂, NH₂, —C(O)R^(a), —C(O)OR^(a),—C(O)NR⁷R⁸, —NR⁸C(O)R^(c), —NR⁸C(O)₂R^(c), —S(O)_(p)NR⁸R⁹,—NR⁸S(O)_(p)R^(c), —S(O)_(p)R^(c), C₁₋₆ alkyl, or —(CH₂)_(r)—C₃₋₁₀carbocycle substituted with 0-3 R^(d); and alternately, when two R^(11b)groups are substituents on adjacent atoms they may be taken togetherwith the atoms to which they are attached to form a 5- to 7-memberedheterocycle comprising carbon atoms and 1-4 heteroatoms selected from N,O, and S(O)_(p) and substituted with 0-2 R^(g).
 5. A compound accordingto claim 4, wherein the compound is of Formula (I) or a stereoisomer,tautomer, pharmaceutically acceptable salt thereof, wherein: A issubstituted with 0-1 R¹ and 0-3 R² and selected from; C₃₋₇ cycloalkyl,phenyl, naphthyl, pyridyl, 1,2,3,4-tetrahydronaphthyl, pyrrolidinyl,indazolyl, indolyl, imidazolyl, furanyl, thienyl, benzimidazolyl,benzisoxazolyl, benzothiazolyl, benzothiophenyl,3,4-methylenedioxy-phenyl, oxazolyl, isoxazolyl, thiazolyl,isothiazolyl, pyrazolyl, quinolinyl, isoquinolinyl,1H-4-oxo-isoquinazolinyl, 2H-1-oxo-isquinilinyl, 3H-4-oxo-quinazolinyl,3,4-dihydro-2H-1-oxo-isoquinolinyl, 2,3-dihydro-isoindolinyl,5,6,7,8-tetrahydroquinolinyl, 1,2,3,4-tetrahydroquinolinyl,5,6,7,8-tetrahydroisoquinolinyl, 1,2,3,4-tetrahydroisoquinolinyl,quinazolinyl, and phthalazinyl; R³ is, independently at each occurrence,phenyl, 3-biphenyl, 4-biphenyl, 3-aminophenyl, 4-aminophenyl,3-N,N-dimethylaminophenyl, 4-phenoxyphenyl, 4-benzyloxyphenyl,4-(t-butoxymethyl)-phenyl, 4-methylsulfonylphenyl, 3-cyanophenyl,4-cyanophenyl, 3-fluorophenyl, 4-fluorophenyl, 3-chlorophenyl,4-chlorophenyl, 3-bromophenyl, 4-bromophenyl, 3-hydroxyphenyl,4-hydroxyphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-methoxyphenyl,3-trifluoromethylphenyl, 4-trifluoromethylphenyl, 3-carboxyphenyl,4-carboxyphenyl, 3-methoxycarbonylphenyl, 4-methoxycarbonylphenyl,3-carboxymethylphenyl, 4-carboxymethylphenyl,4-methoxycarbonylmethylphenyl, 3-ethoxycarbonylmethylphenyl,4-ethoxycarbonylmethylphenyl, 4-ethoxycarbonylethylphenyl,3-carbamoylphenyl, 4-carbamoylphenyl, 3-aminocarbonylmethylphenyl,4-aminocarbonylmethylphenyl, 4-methylaminocarbonylphenyl,4-dimethylaminocarbonylmethylphenyl, 4-amidinophenyl,3-methylcarbonylaminophenyl, 4-methylcarbonylaminophenyl,4-methoxycarbonylaminophenyl, 4-aminosulfonylphenyl,3-methylsulfonylaminophenyl, 4-methylsulfonylamino, 2,4-difluorophenyl,3-fluoro-4-cyanophenyl, 4-amino-3-carboxyphenyl,4-amino-3-methoxycarbonylphenyl, 2,4-dichlorophenyl,3-cyano-5-fluorophenyl, 3-fluoro-4-carbamoylphenyl,3-carboxy-4-cyanophenyl, 3-phenyl-4-carbamoylphenyl,4-(2-oxo-1-piperidino)-phenyl, thiazol-2-yl, thien-2-yl,4-methoxycarbonyl-thiazol-2-yl, 4-carbamoyl-thiazol-2-yl,1-benzyl-pyazol-4-yl, 5-phenyl-oxazol-2-yl, 5-carbamoyl-thien-2-yl,5-carboxy-thien-2-yl, pyrid-2-yl, pyrid-3-yl, pyrid-4-yl,6-amino-pyrid-3-yl, benzimidazol-2-yl, 6-methoxy-pyrid-3-yl,1-methyl-benzimidazol-2-yl, benzoxazol-2-yl, benzothiazol-2-yl,3-amino-benzisoxazol-6-yl, 3-amino-benzisoxazol-5-yl, indazol-5-yl,indazol-6-yl, 3-amino-indazol-5-yl, 3-hydroxy-indazol-5-yl,3-amino-indazol-6-yl, 3-amino-1-methyl-indazol-6-yl,3-amino-4-fluoro-indazol-6-yl, 3-amino-5-fluoro-indazol-6-yl,3-amino-7-fluoro-indazol-6-yl,4-imino-3,4-dihydro-2H-phthalazin-1-on-7-yl, 3-(5-tetrazolyl)-phenyl,2,3-dihydro-isoindol-1-on-6-yl, quinolin-5-yl, quinolin-6-yl,quinolin-8-yl, isoquinolin-5-yl, 2H-isoquinolin-1-on-6-yl,2,4-diaminoquinazolin-7-yl, 4-NH₂-quinazolin-7-yl,

R⁴ is, independently at each occurrence, H, F, Cl, Br, Me, Et, Pr, CN,CF₃, —CH₂OH, —CH₂NH₂, —CO₂H, —C(O)NH₂, —C(O)NHMe, —C(O)N(Me)₂, —CH₂CO₂H,—CH₂C(O)NH₂, or —CH₂CH₂CO₂H; and R¹¹ is cyclohexylmethyl, benzyl,phenethyl, 2-fluorobenzyl, 3-fluorobenzyl, 4-fluorobenzyl,2-chlorobenzyl, 3-chlorobenzyl, 4-chlorobenzyl, 2-bromobenzyl,3-bromobenzyl, 4-bromobenzyl, 3-carboxybenzyl, 3-carbamoylbenzyl,3-(N-methylcarbamoyl)-benzyl, 3-(N-ethylcarbamoyl)-benzyl,3-(N,N-dimethylcarbamoyl)-benzyl, 3-tetrazolyl-benzyl, 2-methylbenzyl,3-methylbenzyl, 4-methylbenzyl, 3-trifluoromethylbenzyl,4-trifluoromethylbenzyl, 2-aminobenzyl, 3-aminobenzyl, 2-nitrobenzyl,3-nitrobenzyl, 4-nitrobenzyl, 3-methoxybenzyl, 4-methoxybenzyl,3-difluoromethoxybenzyl, 2-trifluoromethoxybenzyl,3-trifluoromethoxybenzyl, 2-phenoxybenzyl, 3-phenoxybenzyl,2-benzyloxybenzyl, 3-benzyloxybenzyl, 4-benzyloxybenzyl,4-phenylcarbonylbenzyl, 3-methoxycarbonylbenzyl,3-methylcarbonylamino-benzyl, 2-phenylcarbonylamino-benzyl,2-benzylcarbonylamino-benzyl, 3-benzylcarbonylamino-benzyl,3-(benzoyl-methyl-amino)-benzyl, 3-(2-phenylethyl)carbonylamino-benzyl,2-phenylsulfonylamino-benzyl, 3-phenylsulfonylamino-benzyl,3-[N-methyl-N-phenylaminosulfonyl]-benzyl,3-[benzenesulfonyl-methyl-amino]-benzyl, 3-isobutylaminocarbonyl-benzyl,3-t-butylcarbonylamino-benzyl, 3-isopentylaminocarbnoyl-benzyl,3-(2-methylphenyl)carbamoyl-benzyl, 3-(3-methylphenyl)carbamoyl-benzyl,3-(4-methylphenyl)carbamoyl-benzyl, 3-(4-fluorophenyl)carbamoyl-benzyl,3-(1-naphthyl)carbamoyl-benzyl, 3-benzylcarbamoyl-benzyl,3-(4-chlorophenyl)methylcarbamoyl-benzyl,3-(4-methoxyphenyl)methylcarbamoyl-benzyl,3-(2-phenylethyl)carbamoyl-benzyl,3-[2-(4-methoxyphenyl)ethyl]carbamoyl-benzyl,3-[2-(2-chlorophenyl)ethyl]carbamoyl-benzyl,3-[2-(3-chlorophenyl)ethyl]carbamoyl-benzyl,3-[2-(4-chlorophenyl)ethyl]carbamoyl-benzyl,3-[methyl-(pyridin-2-ylethyl)]carbamoyl-benzyl3-(3-phenylpropyl)carbamoyl-benzyl, 3-(ethyl-methyl-carbamoyl)-benzyl,3-(isopropyl-methyl-carbamoyl)-benzyl,3-(isobutyl-methyl-carbamoyl)-benzyl,3-(methyl-phenyl-carbamoyl)-benzyl,3-[(methyl-(3-methylphenyl)-carbamoyl]-benzyl,3-[methyl-(4-methylphenyl)-carbamoyl]-benzyl,3-(benzyl-methyl-carbamoyl)-benzyl,3-[(3-chlorobenzyl)-methyl-carbamoyl]-benzyl,3-[(4-chlorobenzyl)-methyl-carbamoyl]-benzyl,3-[methyl-phenethyl-carbamoyl)]-benzyl,3-(ethyl-phenyl-carbamoyl)-benzyl, 3-(piperidine-1-carbonyl)-benzyl,3-(4-phenyl-piperidine-1-carbonyl)-benzyl,3-(3,4-dihydro-2H-quinoline-1-carbonyl)-benzyl,3-[(2-methoxyethyl)-methyl-carbamoyl]-benzyl,3-(4-methoxy-piperidine-1-carbonyl)-benzyl,3-(morpholine-4-sulfonyl)-benzyl, 3-[(N-(2-methoxyethyl),N-methylamino)sulfonyl]-benzyl, 3-(N,N-dimethylaminosulfonyl)-benzyl,3-(azetidine-1-carbonyl)-benzyl,3-(3-methoxy-azetidine-1-carbonyl)-benzyl,3-(3-hydroxy-pyrrolidine-1-carbonyl)-benzyl,3-[(4-tetrahydropyranyl)methylcarbonyl]-benzyl,3-[(2-hydroxyethyl)-methyl-carbamoyl]-benzyl,3-(3-hydroxy-azetidine-1-carbpnyl)-benzyl,3-(4-hydroxypiperidine-1-carbonyl)-benzyl,3-[4-(N,N-dimethylamino)-piperidine-1-carbonyl]-benzyl,3-(4-methyl-piperazine-1-carbonyl)-benzyl,3-[3-(N,N-dimethylamino)-pyrrolidine-1-carbonyl]-benzyl,2-phenyl-benzyl, 3-phenyl-benzyl, 4-phenyl-benzyl, 3-phenethyl-benzyl,benzyloxymethyl, benzylthiomethyl, 1-naphthylmethyl, 2-naphthylmethyl,thiazol-4-ylmethyl, pyrid-2-ylmethyl, pyrid-3-ylmethyl,pyrid-4-ylmethyl, 1-benzyl-imidazol-4-ylmethyl, benzothiazol-2-ylmethyl,3-(1-morpholinocarbonyl)-benzyl,3-[(2,6-dimethylmorpholine-4-carbonyl)-benzyl, cyclopropylmethyl,(4-hydroxy)cyclohexylmethyl, 4-oxo-cyclohexylmethyl,


6. A compound according to claim 5, wherein the compound is of Formula(I) or a stereoisomer, tautomer, pharmaceutically acceptable saltthereof, wherein: A is 4-aminomethylcyclohexyl, 4-methylcyclohexyl,4-methoxyphenyl, 4-aminomethylphenyl, 4-carbamoylphenyl,4-amidinophenyl, 2-fluoro-4-methylphenyl, 2,6-difluoro-4-methylphenyl,2-fluoro-4-methoxyphenyl, 2,6-difluoro-4-methoxyphenyl,2-fluoro-4-aminomethylphenyl, 2-fluoro-4-carbamoylphenyl,4-amino-2-fluorophenyl, 4-amino-2,6-difluoromethylphenyl,4-amino-3-chloro-2,3-difluorophenyl, 4-amino-3-chlorophenyl,3-chlorothien-2-yl, indol-5-yl, indol-6-yl, indazol-6-yl,3-aminoindazol-6-yl, 3-aminoindazol-5-yl, 1-methyl-3-aminoindazol-6-yl,3-aminobenzisoxazol-6-yl, benzimidazol-5-yl, 6-fluorobenzimidazol-5-yl,1,2,3,4-tetrahydroisoquinolin-6-yl, 1,2,3,4-tetrahydroisoquinolin-3-yl,2H-isoquinolin-1-on-6-yl, isoquinolin-6-yl, 1-amino-isoquinolin-6-yl,1-amino-3-methyl-isoquinolin-6-yl,1-amino-5,6,7,8-tetrahydroisoquinolin-6-yl, 4-amino-quinazolin-7-yl,3H-quinazolin-4-on-7-yl, 3-chlorophenyl, 3-bromophenyl, 3-methylphenyl,3-methoxyphenyl, 2,5-dichlorophenyl, 5-chloro-2-fluorophenyl,5-bromo-2-fluorophenyl, 3-chloro-2-fluorophenyl,2-methyl-5-chlorophenyl, 2-methoxy-5-chlorophenyl,2-methylthio-5-chlorophenyl, 2-ethylthio-5-chlorophenyl,2-propylthio-5-chlorophenyl, 2-benzylthio-5-chlorophenyl,2-amino-5-chlorophenyl, 2-aminomethyl-5-chlorophenyl,2,6-difluoro-3-methylphenyl, 2-chloro-6-fluoro-3-methylphenyl,2-fluoro-6-chloro-3-methylphenyl, 2,6-difluoro-3-chlorophenyl,2,3-dichloro-6-nitrophenyl, 5-chloro-2-thienyl,3,4-methylenedioxyphenyl, 2-methoxycarbonyl-5-chlorophenyl,6-chlorobenzimidazol-4-yl, 2-(3-carboxypyrazol-1-yl)-5-chlorophenyl,2-(1,2,3-triazol-1-yl)-5-methylphenyl,2-(1,2,3-triazol-1-yl)-5-chlorophenyl,2-(1,2,4-triazol-1-yl)-5-chlorophenyl,2-(1,2,3-triazol-2-yl)-5-chlorophenyl,2-[(4-carboxy)-1,2,3-triazol-1-yl]-5-chlorophenyl,2-[(4-carboxy)-1,2,3-triazol-1-yl]-5-methylphenyl,2-[(4-ethoxycarbonyl)-1,2,3-triazol-1-yl]-5-chlorophenyl,2-(tetrazol-1-yl)-5-methyl-phenyl, 2-(tetrazol-1-yl)-5-chlorophenyl,2-(tetrazol-1-yl)-3-fluoro-5-chlorophenyl,2-(tetrazol-1-yl)-3-fluoro-5-methylphenyl, or2-(5-methyltetrazol-1-yl)-5-chlorophenyl; R³ is, independently at eachoccurrence,

R¹¹ is cyclohexylmethyl, benzyl, phenethyl, 2-fluorobenzyl,3-fluorobenzyl, 4-fluorobenzyl, 2-chlorobenzyl, 3-chlorobenzyl,4-chlorobenzyl, 3-carboxybenzyl, 3-carbamoylbenzyl,3-(N-methylcarbamoyl)-benzyl, 3-(N,N-dimethylcarbamoyl)-benzyl,3-(N-ethylcarbamoyl)-benzyl, 3-methylbenzyl, 4-methylbenzyl,3-methoxybenzyl, 3-difluoromethoxybenzyl, 3-trifluoromethoxy-benzyl,3-methoxycarbonylbenzyl, 3-methylcarbonylamino-benzyl,3-benzylcarbonylamino-benzyl, 3-(benzoyl-methyl-amino)-benzyl,3-(2-phenylethyl)carbonylamino-benzyl, 2-phenylsulfonylamino-benzyl,3-phenylsulfonylamino-benzyl, 3-[N-methyl,N-phenylaminosulfonyl]-benzyl, 3-(benzenesulfonyl-methyl-amino)-benzyl,3-(2-methylphenyl)carbamoyl-benzyl, 3-(3-methylphenyl)carbamoyl-benzyl,3-(4-methylphenyl)carbamoyl-benzyl, 3-(4-fluorophenyl)carbamoyl-benzyl,3-(1-naphthyl)carbamoyl-benzyl, 3-benzylcarbamoyl-benzyl,3-(4-chlorophenyl)methylcarbamoyl-benzyl,3-(4-methoxyphenyl)methylcarbamoyl-benzyl,3-(2-phenylethyl)carbamoyl-benzyl,3-[2-(4-methoxyphenyl)ethyl]carbamoyl-benzyl,3-[2-(2-chlorophenyl)ethyl]carbamoyl-benzyl,3-[2-(3-chlorophenyl)ethyl]carbamoyl-benzyl,3-[2-(4-chlorophenyl)ethyl]carbamoyl-benzyl,3-[methyl-(pyridin-2-ylethyl)]carbamoyl-benzyl3-(3-phenylpropyl)carbamoyl-benzyl, 3-(ethyl-methyl-carbamoyl)-benzyl,3-(isopropyl-methyl-carbamoyl)-benzyl,3-(isobutyl-methyl-carbamoyl)-benzyl,3-(methyl-phenyl-carbamoyl)-benzyl,3-[(methyl-(3-methylphenyl)-carbamoyl]-benzyl,3-[methyl-(4-methylphenyl)-carbamoyl]-benzyl,3-(benzyl-methyl-carbamoyl)-benzyl,3-[(3-chlorobenzyl)-methyl-carbamoyl]-benzyl,3-[(4-chlorobenzyl)-methyl-carbamoyl]-benzyl,3-[methyl-phenethyl-carbamoyl)]-benzyl,3-(ethyl-phenyl-carbamoyl)-benzyl, 3-(piperidine-1-carbonyl)-benzyl,3-(3,4-dihydro-2H-quinoline-1-carbonyl)-benzyl,3-[(2-methoxyethyl)-methyl-carbamoyl]-benzyl,3-(4-methoxy-piperidine-1-carbonyl)-benzyl,3-(morpholine-4-sulfonyl)-benzyl, 3-[(N-(2-methoxyethyl),N-methylamino)sulfonyl]-benzyl, 3-(N,N-dimethylaminosulfonyl)-benzyl,3-(azetidine-1-carbonyl)-benzyl,3-(3-methoxy-azetidine-1-carbonyl)-benzyl,3-(3-hydroxy-pyrrolidine-1-carbonyl)-benzyl,3-[(4-tetrahydropyranyl)methylcarbonyl]-benzyl,3-[(2-hydroxyethyl)-methyl-carbamoyl]-benzyl,3-(3-hydroxy-azetidine-1-carbpnyl)-benzyl,3-(4-hydroxypiperidine-1-carbonyl)-benzyl,3-[4-(N,N-dimethylamino)-piperidine-1-carbonyl]-benzyl,3-(4-methyl-piperazine-1-carbonyl)-benzyl,3-[3-(N,N-dimethylamino)-pyrrolidine-1-carbonyl]-benzyl,1-naphthylmethyl, 2-naphthylmethyl, cyclopropylmethyl,(4-hydroxy)cyclohexylmethyl, 4-oxo-cyclohexylmethyl,


7. A compound according to claim 1, wherein the compound is of Formula(I), or a stereoisomer, tautomer, pharmaceutically acceptable saltthereof, wherein: A is 4-aminomethyl-cyclohexyl,2,6-difluoro-4-methoxyphenyl, or 2-(tetrazol-1-yl)-5-chlorophenyl; L₁ isa bond or —CH═CH—; R⁴ is H or Cl; R³ is 3-carboxy-phenyl,4-carboxy-phenyl, 4-carbamoyl-phenyl, 4-methoxycarbonylamino-phenyl, or3-amino-indazol-6-yl; and R¹¹ is benzyl.
 8. A compound according toclaim 1, wherein the compound is selected from:4-(5-{1-[(trans-4-aminomethyl-cyclohexanecarbonyl)-amino]-2-phenyl-ethyl}-2-chloro-thiophen-3-yl)-benzamide;trans-4-aminomethyl-cyclohexanecarboxylic acid{1-[4-(3-amino-1H-indazol-6-yl)-5-chloro-thiophen-2-yl]-2-phenyl-ethyl}-amide;trans-4-aminomethyl-cyclohexanecarboxylic acid{1-[4-(3-amino-1H-indazol-6-yl)-thiophen-2-yl]-2-phenyl-ethyl}-amide;3-(5-{1-[(trans-4-aminomethyl-cyclohexanecarbonyl)-amino]-2-phenyl-ethyl}-2-chloro-thiophen-3-yl)-benzoicacid;4-(5-{1-[(trans-4-aminomethyl-cyclohexanecarbonyl)-amino]-2-phenyl-ethyl}-2-chloro-thiophen-3-yl)-benzoicacid;[4-(5-{1-[(trans-4-Aminomethyl-cyclohexanecarbonyl)-amino]-2-phenyl-ethyl}-2-chloro-thiophen-3-yl)-phenyl]-carbamicacid methyl ester;(4-{5-[(S)-1-(2,6-difluoro-4-methoxy-benzoylamino)-2-phenyl-ethyl]-thiophen-3-yl}-phenyl)-carbamicacid methyl ester; or a stereoisomer, tautomer, pharmaceuticallyacceptable salt thereof.
 9. A pharmaceutical composition, comprising: apharmaceutically acceptable carrier and a compound of claim 1 or astereoisomer, tautomer, pharmaceutically acceptable salt thereof.